WEBVTT 00:00:00.000 --> 00:00:02.350 align:middle line:84% The following content is provided 00:00:02.350 --> 00:00:06.130 align:middle line:84% by MIT OpenCourseWare under a Creative Commons license. 00:00:06.130 --> 00:00:08.380 align:middle line:84% Additional information about our license 00:00:08.380 --> 00:00:10.720 align:middle line:84% and MIT OpenCourseWare in general 00:00:10.720 --> 00:00:13.146 align:middle line:90% is available at ocw.mit.edu. 00:00:13.146 --> 00:00:16.248 align:middle line:90% 00:00:16.248 --> 00:00:17.790 align:middle line:84% ROBERT WEINBERG: Good morning, class. 00:00:17.790 --> 00:00:18.900 align:middle line:90% Nice to see you again. 00:00:18.900 --> 00:00:22.830 align:middle line:90% Hope you had a great weekend. 00:00:22.830 --> 00:00:25.870 align:middle line:84% If you didn't, it wasn't because of the weather. 00:00:25.870 --> 00:00:29.610 align:middle line:84% So here I am, once again a member of the walking wounded. 00:00:29.610 --> 00:00:32.070 align:middle line:84% And we're talking about carbohydrates today, 00:00:32.070 --> 00:00:33.990 align:middle line:84% as you may recall, or at least we 00:00:33.990 --> 00:00:37.710 align:middle line:84% were at the end of our discussion last time. 00:00:37.710 --> 00:00:42.540 align:middle line:84% And we made the point that these multiple hydroxyl groups 00:00:42.540 --> 00:00:44.550 align:middle line:84% on the carbohydrates, on the one hand, 00:00:44.550 --> 00:00:50.760 align:middle line:84% determine the identity of various kinds of sugars, 00:00:50.760 --> 00:00:53.580 align:middle line:84% just the orientation, the three-dimensional orientation 00:00:53.580 --> 00:00:57.690 align:middle line:84% of them, for one thing, and for another 00:00:57.690 --> 00:01:01.320 align:middle line:84% that these multiple hydroxyl groups represented 00:01:01.320 --> 00:01:03.810 align:middle line:84% the opportunity for forming covalent bonds 00:01:03.810 --> 00:01:06.300 align:middle line:84% with other monosaccharides, as is indicated here 00:01:06.300 --> 00:01:10.020 align:middle line:84% in these disaccharides, or covalent bonds 00:01:10.020 --> 00:01:13.710 align:middle line:84% end to end to create large molecules, which 00:01:13.710 --> 00:01:16.870 align:middle line:84% will increasingly be the theme of our discussion today. 00:01:16.870 --> 00:01:17.370 align:middle line:90% i.e. 00:01:17.370 --> 00:01:19.110 align:middle line:84% When I talk about large molecules, 00:01:19.110 --> 00:01:23.970 align:middle line:84% we just use the phrase generically of macromolecules, 00:01:23.970 --> 00:01:29.160 align:middle line:84% since, in principle, these end to end joinings of molecules, 00:01:29.160 --> 00:01:33.780 align:middle line:84% which involve the dehydration and the formation 00:01:33.780 --> 00:01:36.000 align:middle line:84% of these covalent bonds like right here, 00:01:36.000 --> 00:01:39.160 align:middle line:84% can create molecules that are hundreds indeed even 00:01:39.160 --> 00:01:41.620 align:middle line:90% thousands of subunits long. 00:01:41.620 --> 00:01:43.570 align:middle line:84% So here, if we're talking about a polymer, 00:01:43.570 --> 00:01:47.500 align:middle line:84% we refer to each one of these subunits of the polymer 00:01:47.500 --> 00:01:50.770 align:middle line:84% as being a monomer and the aggregate as a whole 00:01:50.770 --> 00:01:52.650 align:middle line:90% is being a polymer. 00:01:52.650 --> 00:01:57.220 align:middle line:84% And here, we touched upon the fact toward the end of last 00:01:57.220 --> 00:01:59.540 align:middle line:84% lecture-- in fact, at the very end-- 00:01:59.540 --> 00:02:04.130 align:middle line:84% that one can cross-link these long linear chains 00:02:04.130 --> 00:02:05.600 align:middle line:90% of carbohydrates. 00:02:05.600 --> 00:02:07.530 align:middle line:84% Here, we see the fact that glycogen, 00:02:07.530 --> 00:02:10.520 align:middle line:84% which is a form of glucose that is stored 00:02:10.520 --> 00:02:13.910 align:middle line:84% in our liver largely and to a small extent in the muscles, 00:02:13.910 --> 00:02:18.500 align:middle line:90% actually is cross-branched. 00:02:18.500 --> 00:02:22.130 align:middle line:84% If one draws on a much smaller scale glycogen molecule, 00:02:22.130 --> 00:02:25.100 align:middle line:84% one might draw a picture that looks like this, 00:02:25.100 --> 00:02:27.080 align:middle line:84% that it looks almost like a Christmas tree 00:02:27.080 --> 00:02:28.700 align:middle line:90% with multiple branches. 00:02:28.700 --> 00:02:30.860 align:middle line:84% And the purpose of this is actually 00:02:30.860 --> 00:02:34.190 align:middle line:84% to sequester the glucose, to store the glucose 00:02:34.190 --> 00:02:38.030 align:middle line:84% in a metabolically inactive form, until the time comes 00:02:38.030 --> 00:02:40.170 align:middle line:84% that the organism needs, once again, 00:02:40.170 --> 00:02:42.320 align:middle line:84% the energy that is stored in the glucose, 00:02:42.320 --> 00:02:45.500 align:middle line:84% upon which occasion these bonds are rapidly broken down, 00:02:45.500 --> 00:02:47.660 align:middle line:84% and the glucose is mobilized and put 00:02:47.660 --> 00:02:50.600 align:middle line:84% into the circulation for eventual disposition 00:02:50.600 --> 00:02:53.690 align:middle line:84% and use in certain specific tissues. 00:02:53.690 --> 00:02:57.860 align:middle line:84% While it's encumbered in these high molecular weight polymers, 00:02:57.860 --> 00:03:00.920 align:middle line:84% the glucose is essentially metabolically inactive. 00:03:00.920 --> 00:03:03.350 align:middle line:84% The body doesn't realize it's there. 00:03:03.350 --> 00:03:06.950 align:middle line:84% And we can, as a consequence, store large amounts of energy 00:03:06.950 --> 00:03:08.630 align:middle line:90% in these glycogen molecules. 00:03:08.630 --> 00:03:12.020 align:middle line:84% And it can be stored there indefinitely. 00:03:12.020 --> 00:03:16.390 align:middle line:84% Now, the fact is that this idea end 00:03:16.390 --> 00:03:19.630 align:middle line:84% to end polymerization that I just mentioned 00:03:19.630 --> 00:03:22.570 align:middle line:84% can be extended to other macromolecules, which 00:03:22.570 --> 00:03:28.570 align:middle line:84% also become linked end to end in specific kinds of polymers. 00:03:28.570 --> 00:03:31.720 align:middle line:84% And here, we are moving now into the notion 00:03:31.720 --> 00:03:33.770 align:middle line:90% of talking about amino acids. 00:03:33.770 --> 00:03:36.100 align:middle line:84% And we're talking about proteins. 00:03:36.100 --> 00:03:38.800 align:middle line:84% If we look at an amino acid, what we see 00:03:38.800 --> 00:03:42.590 align:middle line:84% is it has an important structure like this. 00:03:42.590 --> 00:03:45.940 align:middle line:84% Here's a central carbon and four, 00:03:45.940 --> 00:03:49.060 align:middle line:84% in principle, distinct side chains, 00:03:49.060 --> 00:03:51.730 align:middle line:84% where r represents some side chain that 00:03:51.730 --> 00:03:53.830 align:middle line:84% can be any one of-- as we'll see shortly, 00:03:53.830 --> 00:03:57.460 align:middle line:84% any one of 20 distinct identities. 00:03:57.460 --> 00:04:01.120 align:middle line:84% But all the amino acids share in common the property 00:04:01.120 --> 00:04:03.230 align:middle line:84% that they have this overall structure. 00:04:03.230 --> 00:04:08.170 align:middle line:84% And as you may recall from our discussion of last week, 00:04:08.170 --> 00:04:11.885 align:middle line:84% at neutral pH, it wouldn't-- an amino acid of this sort, 00:04:11.885 --> 00:04:14.900 align:middle line:84% whatever [? r-ase, ?] wouldn't look like this at all 00:04:14.900 --> 00:04:18.050 align:middle line:84% because the amine group would attract an extra proton, 00:04:18.050 --> 00:04:20.300 align:middle line:84% causing it to become positively charged. 00:04:20.300 --> 00:04:23.840 align:middle line:84% And the carboxyl group would release a proton, 00:04:23.840 --> 00:04:26.310 align:middle line:84% causing it to become negatively charged. 00:04:26.310 --> 00:04:30.290 align:middle line:84% And as you might deduce from this, at very low pH, 00:04:30.290 --> 00:04:33.290 align:middle line:84% due to the greatly increased concentration of protons, 00:04:33.290 --> 00:04:35.840 align:middle line:84% free protons in the solution, the equilibrium 00:04:35.840 --> 00:04:39.260 align:middle line:84% would be driven more in favor of reattaching 00:04:39.260 --> 00:04:42.440 align:middle line:84% a proton to the carboxyl group, just because there are so 00:04:42.440 --> 00:04:44.570 align:middle line:90% many of these protons around. 00:04:44.570 --> 00:04:49.520 align:middle line:84% Conversely, at very high pH, where the hydroxyl ions are 00:04:49.520 --> 00:04:54.020 align:middle line:84% in predominance, they obviously tend to scavenge protons, 00:04:54.020 --> 00:04:58.250 align:middle line:84% reducing the level of protons to a very low level in the water. 00:04:58.250 --> 00:05:00.410 align:middle line:84% And under very high pH conditions, 00:05:00.410 --> 00:05:02.930 align:middle line:84% this proton would be released and pulled away 00:05:02.930 --> 00:05:06.740 align:middle line:84% by the hydroxyl ions, causing this amine group, once again, 00:05:06.740 --> 00:05:10.860 align:middle line:84% to return to its negative charge state. 00:05:10.860 --> 00:05:16.665 align:middle line:84% Now, the fact of the matter is that these amino acids 00:05:16.665 --> 00:05:19.200 align:middle line:84% exist in a very specific three-dimensional 00:05:19.200 --> 00:05:20.190 align:middle line:90% configuration. 00:05:20.190 --> 00:05:22.500 align:middle line:84% And that's illustrated much more nicely here 00:05:22.500 --> 00:05:25.980 align:middle line:84% than I could possibly draw on the board, which in any case 00:05:25.980 --> 00:05:29.520 align:middle line:84% would be hopeless, which is that you can see 00:05:29.520 --> 00:05:32.670 align:middle line:84% in principle that once you have four distinct side 00:05:32.670 --> 00:05:36.060 align:middle line:84% groups coming off of a carbon, that there's, in principle, two 00:05:36.060 --> 00:05:39.750 align:middle line:90% different ways to create them. 00:05:39.750 --> 00:05:42.270 align:middle line:84% And this is sometimes called chirality. 00:05:42.270 --> 00:05:44.520 align:middle line:84% Chiral you see is the form right here. 00:05:44.520 --> 00:05:46.050 align:middle line:90% The hands are chiral. 00:05:46.050 --> 00:05:49.860 align:middle line:84% If I try as much as I will to superimpose one hand on top 00:05:49.860 --> 00:05:52.590 align:middle line:84% of another, it doesn't work because they're 00:05:52.590 --> 00:05:55.350 align:middle line:84% mirror images of one another, which are asymmetrical. 00:05:55.350 --> 00:05:58.380 align:middle line:84% And as a consequence, we see a similar kind of relationship 00:05:58.380 --> 00:06:03.540 align:middle line:84% occurring here, where we see that these two 00:06:03.540 --> 00:06:07.570 align:middle line:84% forms of amino acids could, in principle, exist. 00:06:07.570 --> 00:06:09.390 align:middle line:84% And they're not interchangeable, unless one 00:06:09.390 --> 00:06:12.300 align:middle line:84% breaks one of the bonds and reforms it. 00:06:12.300 --> 00:06:14.610 align:middle line:84% These two forms are called the L and the D. 00:06:14.610 --> 00:06:17.370 align:middle line:84% And it out that the L form is the one that's 00:06:17.370 --> 00:06:21.060 align:middle line:84% used by virtually all life forms on the planet, i.e. there was 00:06:21.060 --> 00:06:23.610 align:middle line:84% an arbitrary choice made some time 00:06:23.610 --> 00:06:26.280 align:middle line:84% about 3 billion years ago and more to use 00:06:26.280 --> 00:06:29.760 align:middle line:84% one of the two three-dimensional configurations 00:06:29.760 --> 00:06:31.470 align:middle line:90% and not to use the other. 00:06:31.470 --> 00:06:33.720 align:middle line:84% The other is found in certain rare exceptions. 00:06:33.720 --> 00:06:37.590 align:middle line:84% But virtually all life forms on this planet use the L form. 00:06:37.590 --> 00:06:39.570 align:middle line:84% That said, by the way, this begins 00:06:39.570 --> 00:06:43.470 align:middle line:84% to indicate some of the arbitrary decisions that 00:06:43.470 --> 00:06:46.590 align:middle line:84% were made early during evolution because we could imagine, 00:06:46.590 --> 00:06:49.480 align:middle line:84% on another planet, if life were to exist there 00:06:49.480 --> 00:06:52.410 align:middle line:84% and if it were to depend on amino acids, 00:06:52.410 --> 00:06:55.540 align:middle line:84% that evolutionary system might have chosen the D form. 00:06:55.540 --> 00:06:57.540 align:middle line:90% So this is a luck of the draw. 00:06:57.540 --> 00:07:01.460 align:middle line:84% This is actually the way things evolved here. 00:07:01.460 --> 00:07:06.500 align:middle line:84% And what we begin to see now is, if we talk about proteins or-- 00:07:06.500 --> 00:07:09.830 align:middle line:84% if we want to be more specific and use the more biochemical 00:07:09.830 --> 00:07:11.960 align:middle line:90% term, polypeptide-- 00:07:11.960 --> 00:07:13.730 align:middle line:84% we see, once again, we have an end 00:07:13.730 --> 00:07:17.540 align:middle line:84% to end n joining system, which is a bit different from that 00:07:17.540 --> 00:07:20.780 align:middle line:84% which the monosaccharides employ to create 00:07:20.780 --> 00:07:24.080 align:middle line:84% long chains of glycogen or of starch 00:07:24.080 --> 00:07:27.470 align:middle line:84% because here we see, once again, a dehydration reaction, 00:07:27.470 --> 00:07:30.890 align:middle line:84% where an amine group and a carboxyl group 00:07:30.890 --> 00:07:35.550 align:middle line:84% are caused to shed the hydroxyl and the proton, 00:07:35.550 --> 00:07:38.680 align:middle line:84% causing the formation of a peptide bond. 00:07:38.680 --> 00:07:40.980 align:middle line:84% And here, we see this important, very important 00:07:40.980 --> 00:07:44.010 align:middle line:84% biochemical entity, a peptide bond consisting here 00:07:44.010 --> 00:07:48.270 align:middle line:84% of this carbonyl and this nitrogen fused 00:07:48.270 --> 00:07:49.890 align:middle line:90% in this specific way. 00:07:49.890 --> 00:07:52.980 align:middle line:84% And of course, if you recognize this as being a peptide bond, 00:07:52.980 --> 00:07:56.250 align:middle line:84% then you can understand why proteins are sometimes 00:07:56.250 --> 00:07:59.130 align:middle line:90% given the term polypeptide. 00:07:59.130 --> 00:08:02.280 align:middle line:84% In some cases, if one has very short stretches 00:08:02.280 --> 00:08:05.430 align:middle line:84% of amino acids linked end to end like this, 00:08:05.430 --> 00:08:08.310 align:middle line:84% we talk about these being oligopeptides, 00:08:08.310 --> 00:08:11.820 align:middle line:84% where oligo- is the general term used in biology to refer 00:08:11.820 --> 00:08:14.160 align:middle line:84% to a small number of things rather than 00:08:14.160 --> 00:08:16.690 align:middle line:90% a large number of things. 00:08:16.690 --> 00:08:19.170 align:middle line:84% And once again, we have here the possibility 00:08:19.170 --> 00:08:20.940 align:middle line:90% of extending this infinitely. 00:08:20.940 --> 00:08:22.830 align:middle line:84% There are no constraints, in principle, 00:08:22.830 --> 00:08:27.630 align:middle line:84% on making this 500, a 1,000, even 2,000 amino acids long, 00:08:27.630 --> 00:08:30.330 align:middle line:84% where each of these, once again, is an amino acid. 00:08:30.330 --> 00:08:32.669 align:middle line:84% And once again, I'm being very coy 00:08:32.669 --> 00:08:35.590 align:middle line:84% about the identities of R1 and R2, 00:08:35.590 --> 00:08:38.140 align:middle line:84% which, as I will indicate very shortly, 00:08:38.140 --> 00:08:41.380 align:middle line:84% can be one of 20 distinct alternatives. 00:08:41.380 --> 00:08:44.440 align:middle line:84% Here, you see that we're continuing this process 00:08:44.440 --> 00:08:46.900 align:middle line:90% of peptide bond formation. 00:08:46.900 --> 00:08:50.380 align:middle line:84% And most importantly here is the realization 00:08:50.380 --> 00:08:54.400 align:middle line:84% that there is a polarity of elongation here. 00:08:54.400 --> 00:08:56.530 align:middle line:84% It doesn't move with equal probability 00:08:56.530 --> 00:08:58.300 align:middle line:90% left or right or right to left. 00:08:58.300 --> 00:09:00.503 align:middle line:90% We start at the amino end here. 00:09:00.503 --> 00:09:01.420 align:middle line:90% This is the amino end. 00:09:01.420 --> 00:09:03.940 align:middle line:84% And this is the carboxyl end-- the amino end 00:09:03.940 --> 00:09:05.230 align:middle line:90% and the carboxyl end. 00:09:05.230 --> 00:09:08.020 align:middle line:84% And invariably, again because of the way life 00:09:08.020 --> 00:09:11.080 align:middle line:84% has evolved on this planet, the new amino acid 00:09:11.080 --> 00:09:13.520 align:middle line:90% is added on the carboxyl end. 00:09:13.520 --> 00:09:16.870 align:middle line:84% And so when one often talks about proteins, 00:09:16.870 --> 00:09:24.760 align:middle line:84% one refers to their N-terminal and to their C-terminal ends, 00:09:24.760 --> 00:09:27.970 align:middle line:84% these referring, obviously, to the amino group at one end 00:09:27.970 --> 00:09:30.230 align:middle line:84% and the carboxyl end at the other end. 00:09:30.230 --> 00:09:34.060 align:middle line:84% So the polarity is always a directed synthesis adding it 00:09:34.060 --> 00:09:35.260 align:middle line:90% on the C-terminal end. 00:09:35.260 --> 00:09:39.070 align:middle line:84% In other words, to use a shorthand notation, 00:09:39.070 --> 00:09:43.240 align:middle line:84% we think about protein synthesis as going with this polarity, 00:09:43.240 --> 00:09:46.750 align:middle line:84% end toward C. Things are growing at the C-terminal end 00:09:46.750 --> 00:09:48.040 align:middle line:90% progressively. 00:09:48.040 --> 00:09:53.030 align:middle line:84% And each time, one can imagine the addition of an amino acids 00:09:53.030 --> 00:09:53.850 align:middle line:90% on the end of it. 00:09:53.850 --> 00:09:57.530 align:middle line:84% So again, it can be extended in principle indefinitely. 00:09:57.530 --> 00:10:00.230 align:middle line:84% Keep in mind as well something that's implicit in everything 00:10:00.230 --> 00:10:03.200 align:middle line:84% I'm telling you, but I won't always mention it explicitly. 00:10:03.200 --> 00:10:06.200 align:middle line:84% And that is virtually every biochemical reaction 00:10:06.200 --> 00:10:08.230 align:middle line:90% is reversible. 00:10:08.230 --> 00:10:12.790 align:middle line:84% And therefore, if one is able to form a peptide bond, 00:10:12.790 --> 00:10:16.630 align:middle line:84% one is able to break it down by biological means as well, i.e. 00:10:16.630 --> 00:10:20.980 align:middle line:84% by introducing a water molecule back in and thereby 00:10:20.980 --> 00:10:24.250 align:middle line:84% using the process of hydrolysis, which 00:10:24.250 --> 00:10:26.890 align:middle line:84% is the breakdown of a bond through the introduction 00:10:26.890 --> 00:10:32.620 align:middle line:84% of a water molecule, to destroy the previously created bond. 00:10:32.620 --> 00:10:35.410 align:middle line:84% To use an MIT phrase, the reversibility 00:10:35.410 --> 00:10:39.820 align:middle line:84% is intuitively obvious because if you are able to make a-- 00:10:39.820 --> 00:10:42.130 align:middle line:84% well, I don't know if it's still used. 00:10:42.130 --> 00:10:45.220 align:middle line:84% But it was used in the late Stone Age around here. 00:10:45.220 --> 00:10:48.660 align:middle line:84% Anyhow, so any biochemical action 00:10:48.660 --> 00:10:50.910 align:middle line:84% must be reversible because if, for example, 00:10:50.910 --> 00:10:53.610 align:middle line:84% this polymerization were irreversible, 00:10:53.610 --> 00:10:55.410 align:middle line:84% then all the protein that was ever 00:10:55.410 --> 00:10:57.840 align:middle line:84% synthesized on the surface of the planet over the last 3.5 00:10:57.840 --> 00:10:59.970 align:middle line:84% billion years would accumulate progressively. 00:10:59.970 --> 00:11:01.740 align:middle line:84% And obviously, that doesn't happen. 00:11:01.740 --> 00:11:05.160 align:middle line:84% And therefore, macromolecular synthesis, to the extent 00:11:05.160 --> 00:11:08.490 align:middle line:84% it proceeds forward, obviously must go in the other direction 00:11:08.490 --> 00:11:09.700 align:middle line:90% as well. 00:11:09.700 --> 00:11:12.600 align:middle line:84% And the resulting concentration of a complete protein 00:11:12.600 --> 00:11:15.250 align:middle line:90% is known as its steady state. 00:11:15.250 --> 00:11:18.970 align:middle line:84% So we might make a protein at one rate 00:11:18.970 --> 00:11:20.560 align:middle line:84% and break it down at the same rate. 00:11:20.560 --> 00:11:23.260 align:middle line:84% And its steady state concentration 00:11:23.260 --> 00:11:25.750 align:middle line:84% represents the compromise between these two, 00:11:25.750 --> 00:11:28.480 align:middle line:84% i.e. the concentration of such a protein 00:11:28.480 --> 00:11:31.330 align:middle line:84% that we might observe at any one point in time. 00:11:31.330 --> 00:11:32.950 align:middle line:84% Indeed, the term steady state could 00:11:32.950 --> 00:11:36.970 align:middle line:84% be expanded to any process in which there's a synthesis 00:11:36.970 --> 00:11:40.240 align:middle line:84% and there's a breakdown of something and the equilibrium 00:11:40.240 --> 00:11:43.600 align:middle line:84% concentration, which results is, once again, 00:11:43.600 --> 00:11:47.270 align:middle line:84% called the steady state of that molecule. 00:11:47.270 --> 00:11:51.490 align:middle line:84% Now, let's get down to the nitty gritty, which is obviously 00:11:51.490 --> 00:11:54.220 align:middle line:84% something which we can't avoid for very long, which is to say 00:11:54.220 --> 00:11:57.140 align:middle line:90% the R's, i.e. the side chains. 00:11:57.140 --> 00:12:00.650 align:middle line:84% Once again, here, we see an arbitrary artifact 00:12:00.650 --> 00:12:03.740 align:middle line:84% of very early evolution in the biosphere 00:12:03.740 --> 00:12:08.210 align:middle line:84% because there are, in effect, 20 different side chains creating 00:12:08.210 --> 00:12:11.540 align:middle line:84% 20 distinct amino acids, which are 00:12:11.540 --> 00:12:15.330 align:middle line:84% used in proteins by all organisms on this planet. 00:12:15.330 --> 00:12:17.400 align:middle line:84% Again, there are rare exceptions. 00:12:17.400 --> 00:12:20.280 align:middle line:84% Certain fungi and certain bacteria 00:12:20.280 --> 00:12:22.560 align:middle line:84% are able to make unusual amino acids. 00:12:22.560 --> 00:12:25.560 align:middle line:84% But these are the basic building blocks of virtually all life 00:12:25.560 --> 00:12:27.060 align:middle line:90% forms on the planet. 00:12:27.060 --> 00:12:30.520 align:middle line:84% 99.99% of all the protein that is created 00:12:30.520 --> 00:12:34.890 align:middle line:84% is synthesized through the polymerization of these 20 00:12:34.890 --> 00:12:36.690 align:middle line:90% amino acids. 00:12:36.690 --> 00:12:40.710 align:middle line:84% And by the way, one of the amino acids, glycine-- 00:12:40.710 --> 00:12:42.930 align:middle line:84% over here, you see it right here-- 00:12:42.930 --> 00:12:45.810 align:middle line:90% violates this rule of chirality. 00:12:45.810 --> 00:12:48.630 align:middle line:84% And you will recall before, I said that because there 00:12:48.630 --> 00:12:52.920 align:middle line:90% are four distinct amino acid-- 00:12:52.920 --> 00:12:56.250 align:middle line:84% four distinct side chains around the central carbon, sometimes 00:12:56.250 --> 00:12:57.930 align:middle line:84% called the alpha carbon, you always 00:12:57.930 --> 00:13:01.080 align:middle line:84% have a handedness of amino acids. 00:13:01.080 --> 00:13:04.590 align:middle line:84% This cannot this notion cannot be respected in the case 00:13:04.590 --> 00:13:09.518 align:middle line:84% of glycine, seen up here, simply because we don't have four 00:13:09.518 --> 00:13:11.060 align:middle line:84% distinct-- here's the central carbon, 00:13:11.060 --> 00:13:12.393 align:middle line:90% where I'm pointing with the red. 00:13:12.393 --> 00:13:16.315 align:middle line:84% And here, these two hydrogens are equivalent to one another. 00:13:16.315 --> 00:13:17.690 align:middle line:84% They're not four distinct chains. 00:13:17.690 --> 00:13:19.357 align:middle line:84% There's only three distinct chains here. 00:13:19.357 --> 00:13:22.130 align:middle line:84% So glycine violates this rule of chirality, 00:13:22.130 --> 00:13:24.590 align:middle line:90% of left and right-handedness. 00:13:24.590 --> 00:13:27.240 align:middle line:84% And here, by the way the side chain, 00:13:27.240 --> 00:13:30.680 align:middle line:84% which in all of these cases is depicted as extending off 00:13:30.680 --> 00:13:33.170 align:middle line:84% to the right of each amino acid, the side chain 00:13:33.170 --> 00:13:37.990 align:middle line:84% is simply an H, simply a proton, a hydrogen atom. 00:13:37.990 --> 00:13:41.820 align:middle line:84% In fact, what we see about these amino acids 00:13:41.820 --> 00:13:44.880 align:middle line:84% is that the side chains have quite distinct 00:13:44.880 --> 00:13:46.680 align:middle line:90% biochemical properties. 00:13:46.680 --> 00:13:50.070 align:middle line:84% And that begins to impress us with the notion 00:13:50.070 --> 00:13:53.220 align:middle line:84% that proteins and their biochemical attributes 00:13:53.220 --> 00:13:56.220 align:middle line:84% can be dictated by the identities 00:13:56.220 --> 00:13:59.080 align:middle line:84% of the amino acids that are used to construct them. 00:13:59.080 --> 00:14:01.750 align:middle line:84% We can talk about the notion of nonpolar 00:14:01.750 --> 00:14:05.170 align:middle line:90% versus polar amino acids, i.e. 00:14:05.170 --> 00:14:09.490 align:middle line:84% amino acids which have poor affinity for water-- 00:14:09.490 --> 00:14:14.930 align:middle line:84% they don't have a separation of plus and minus charges. 00:14:14.930 --> 00:14:19.160 align:middle line:84% And as a consequence, they're a little bit, or quite 00:14:19.160 --> 00:14:21.420 align:middle line:90% a bit hydrophobic. 00:14:21.420 --> 00:14:23.660 align:middle line:84% Now, you will say, well, how can they be hydrophobic? 00:14:23.660 --> 00:14:25.700 align:middle line:84% Because here, this oxygen is charged 00:14:25.700 --> 00:14:28.100 align:middle line:84% and here this amine group is charged. 00:14:28.100 --> 00:14:30.380 align:middle line:84% That would make it highly hydrophilic. 00:14:30.380 --> 00:14:32.420 align:middle line:84% But keep in mind, when I'm talking 00:14:32.420 --> 00:14:35.210 align:middle line:84% about these amino acids, I'm not talking about them 00:14:35.210 --> 00:14:37.370 align:middle line:84% when they're in a single amino acid form. 00:14:37.370 --> 00:14:39.470 align:middle line:84% I'm talking about their properties 00:14:39.470 --> 00:14:43.530 align:middle line:84% once they have been polymerized into a state like this. 00:14:43.530 --> 00:14:48.050 align:middle line:84% And once they're polymerized into a state like this, 00:14:48.050 --> 00:14:52.130 align:middle line:84% the NH2 and CO charging that is, the charge here and the charge 00:14:52.130 --> 00:14:54.890 align:middle line:84% here become irrelevant because this oxygen. 00:14:54.890 --> 00:14:57.950 align:middle line:84% And this amine group are both tied up in covalent bonds. 00:14:57.950 --> 00:15:03.110 align:middle line:84% And this acquisition of a proton and this shedding of a proton 00:15:03.110 --> 00:15:07.340 align:middle line:84% over here cannot occur because both of these atoms, O and N, 00:15:07.340 --> 00:15:09.510 align:middle line:90% are involved in covalent bonds. 00:15:09.510 --> 00:15:13.310 align:middle line:84% So therefore, when we talk about non-polar 00:15:13.310 --> 00:15:15.540 align:middle line:84% and polar amino acids, keep in mind, 00:15:15.540 --> 00:15:18.420 align:middle line:84% we're focusing on the biochemical properties 00:15:18.420 --> 00:15:21.960 align:middle line:84% of the side chain because the central backbone 00:15:21.960 --> 00:15:25.080 align:middle line:84% of the polypeptide-- and the central backbone 00:15:25.080 --> 00:15:26.853 align:middle line:90% is defined quite clearly here. 00:15:26.853 --> 00:15:28.020 align:middle line:90% Here's the central backbone. 00:15:28.020 --> 00:15:31.290 align:middle line:84% And you see it has a quite repeating structure-- 00:15:31.290 --> 00:15:37.230 align:middle line:84% N-C-C, N-C-C, N-C-C. This is invariant. 00:15:37.230 --> 00:15:41.820 align:middle line:84% What changes and what defines the biochemical attributes 00:15:41.820 --> 00:15:46.392 align:middle line:84% of this oligopeptide or a polypeptide are the identities 00:15:46.392 --> 00:15:47.850 align:middle line:84% of these side chains, which, again, 00:15:47.850 --> 00:15:49.882 align:middle line:84% are plotted on this particular graph-- 00:15:49.882 --> 00:15:51.840 align:middle line:84% and you have a different version in your book-- 00:15:51.840 --> 00:15:53.490 align:middle line:90% off to the right. 00:15:53.490 --> 00:15:57.845 align:middle line:84% Here, you see we have a proton, a methyl group, a valine, 00:15:57.845 --> 00:16:00.480 align:middle line:90% a leucine, an isoleucine. 00:16:00.480 --> 00:16:02.910 align:middle line:84% And the differences between this suggest 00:16:02.910 --> 00:16:08.760 align:middle line:84% these are all quite aliphatic, quite 00:16:08.760 --> 00:16:13.320 align:middle line:84% similar to the propane that we talked 00:16:13.320 --> 00:16:15.150 align:middle line:90% about last time or the hexane. 00:16:15.150 --> 00:16:18.330 align:middle line:84% That is to say, these are quite hydrophobic side groups. 00:16:18.330 --> 00:16:22.770 align:middle line:84% And as such, if there were a polypeptide, we can imagine 00:16:22.770 --> 00:16:25.120 align:middle line:84% and you put the polypeptide in water, 00:16:25.120 --> 00:16:28.140 align:middle line:84% we can imagine that these amino acids would not 00:16:28.140 --> 00:16:31.140 align:middle line:84% like to be directly confronting the water because of the fact 00:16:31.140 --> 00:16:32.970 align:middle line:90% that they're hydrophobic. 00:16:32.970 --> 00:16:36.880 align:middle line:84% Methionine is also a bit hydrophobic. 00:16:36.880 --> 00:16:42.310 align:middle line:84% I'm equivocating there because the S has a slight degree 00:16:42.310 --> 00:16:44.740 align:middle line:90% of hydrophilicity. 00:16:44.740 --> 00:16:46.910 align:middle line:84% It has a slight degree of polarity, 00:16:46.910 --> 00:16:48.220 align:middle line:90% but not really that much. 00:16:48.220 --> 00:16:50.735 align:middle line:84% And these aromatic side chains here, 00:16:50.735 --> 00:16:52.360 align:middle line:84% because they have these benzene rings-- 00:16:52.360 --> 00:16:55.420 align:middle line:84% and those consequently are called aromatic-- 00:16:55.420 --> 00:16:58.510 align:middle line:84% these are quite highly strongly hydrophobic. 00:16:58.510 --> 00:17:03.560 align:middle line:84% So they really hate to be in the intimate contact with water. 00:17:03.560 --> 00:17:06.560 align:middle line:84% Here, on the other hand, let's look at these side chains 00:17:06.560 --> 00:17:13.579 align:middle line:84% because here we have strongly polar molecules, 00:17:13.579 --> 00:17:14.960 align:middle line:90% side chains again. 00:17:14.960 --> 00:17:17.210 align:middle line:84% Keep in mind, we're focusing on the side chains. 00:17:17.210 --> 00:17:19.880 align:middle line:84% Here, we see serine with a hydroxyl group that can form 00:17:19.880 --> 00:17:22.099 align:middle line:84% hydrogen bonds with the water, threonine, 00:17:22.099 --> 00:17:25.490 align:middle line:84% which has its own hydroxyl group, asparagine, 00:17:25.490 --> 00:17:28.850 align:middle line:84% which has two atoms here-- this carbonyl and the NH2-- 00:17:28.850 --> 00:17:31.970 align:middle line:84% both of which can form hydrogen bonds 00:17:31.970 --> 00:17:35.300 align:middle line:84% with the water, as can glutamine. 00:17:35.300 --> 00:17:37.370 align:middle line:90% So these are quite hydrophilic. 00:17:37.370 --> 00:17:40.520 align:middle line:84% They're not as fanatically hydrophilic 00:17:40.520 --> 00:17:43.580 align:middle line:84% as these charged molecules, where the side chains are not 00:17:43.580 --> 00:17:46.160 align:middle line:84% just capable of forming hydrogen bonds. 00:17:46.160 --> 00:17:48.620 align:middle line:84% In this lower group here, the side chains 00:17:48.620 --> 00:17:50.750 align:middle line:84% are capable of undergoing ionization. 00:17:50.750 --> 00:17:52.940 align:middle line:84% So they're actually strongly charged. 00:17:52.940 --> 00:17:57.670 align:middle line:84% And here, we see here the carboxyl group 00:17:57.670 --> 00:18:00.020 align:middle line:84% in aspartic and glutamic acid has actually 00:18:00.020 --> 00:18:03.630 align:middle line:84% discharged its proton, becoming negatively charged. 00:18:03.630 --> 00:18:07.310 align:middle line:84% These are acidic amino acids by virtue of the carboxyl groups 00:18:07.310 --> 00:18:07.850 align:middle line:90% they have. 00:18:07.850 --> 00:18:10.040 align:middle line:90% Basic amino acids here-- 00:18:10.040 --> 00:18:13.430 align:middle line:84% arginine, lysine, and histidine-- all 00:18:13.430 --> 00:18:15.920 align:middle line:84% acquire a positively charged side chain 00:18:15.920 --> 00:18:18.720 align:middle line:84% by virtue of these nitrogens here, 00:18:18.720 --> 00:18:21.680 align:middle line:84% which have a strong affinity for pulling away protons, 00:18:21.680 --> 00:18:25.650 align:middle line:84% for abstracting protons from the aqueous solvent. 00:18:25.650 --> 00:18:30.110 align:middle line:84% And so we have a whole gradient of hydrophilicity 00:18:30.110 --> 00:18:32.480 align:middle line:90% down to hydrophobicity. 00:18:32.480 --> 00:18:35.130 align:middle line:84% And here, we have intermediate structures. 00:18:35.130 --> 00:18:38.990 align:middle line:84% We also have some very special idiosyncratic kinds 00:18:38.990 --> 00:18:40.070 align:middle line:90% of amino acids. 00:18:40.070 --> 00:18:41.420 align:middle line:90% Here is tyrosine. 00:18:41.420 --> 00:18:43.670 align:middle line:84% And tyrosine is a little bit schizophrenic. 00:18:43.670 --> 00:18:47.240 align:middle line:84% Again, it has this highly hydrophobic aromatic group 00:18:47.240 --> 00:18:50.090 align:middle line:84% here, the benzene ring, which hates to be in water, 00:18:50.090 --> 00:18:53.070 align:middle line:84% and the hydroxyl group, which actually is a friend of water. 00:18:53.070 --> 00:18:57.470 align:middle line:84% So here, we have something where its role is quite equivocal. 00:18:57.470 --> 00:19:01.070 align:middle line:84% Here, we have cysteine, as indicated here. 00:19:01.070 --> 00:19:04.050 align:middle line:84% And what's interesting about the cysteine group, in this case, 00:19:04.050 --> 00:19:07.380 align:middle line:84% is the SH group, the side chain, the SH group, 00:19:07.380 --> 00:19:11.640 align:middle line:84% because this group is able to form bonds 00:19:11.640 --> 00:19:14.970 align:middle line:84% with yet other groups from other cysteines. 00:19:14.970 --> 00:19:18.240 align:middle line:84% So let's just look at this cysteine here for a moment. 00:19:18.240 --> 00:19:21.150 align:middle line:84% You see there's a CH2, and then there's an SH. 00:19:21.150 --> 00:19:24.000 align:middle line:84% So let's imagine-- I'm not going to draw all the atoms here. 00:19:24.000 --> 00:19:25.980 align:middle line:84% But let's imagine here we have a CH2 group-- 00:19:25.980 --> 00:19:27.750 align:middle line:90% I'm not drawing the backbone-- 00:19:27.750 --> 00:19:29.100 align:middle line:90% SH over here. 00:19:29.100 --> 00:19:31.380 align:middle line:84% And we could imagine another protein chain, 00:19:31.380 --> 00:19:34.200 align:middle line:84% another polypeptide chain down here-- again, 00:19:34.200 --> 00:19:37.220 align:middle line:90% I'm not drawing the backbone. 00:19:37.220 --> 00:19:38.990 align:middle line:90% But I'm drawing another SH-- 00:19:38.990 --> 00:19:40.440 align:middle line:90% like this. 00:19:40.440 --> 00:19:42.440 align:middle line:84% And the fact is, under the conditions 00:19:42.440 --> 00:19:45.410 align:middle line:84% of oxidation and reduction that operate, 00:19:45.410 --> 00:19:47.780 align:middle line:84% at least in the extracellular space, 00:19:47.780 --> 00:19:51.560 align:middle line:84% one can oxidize these two, resulting 00:19:51.560 --> 00:19:55.235 align:middle line:84% in the formation of what is known as a disulfide bond. 00:19:55.235 --> 00:19:59.800 align:middle line:90% 00:19:59.800 --> 00:20:04.110 align:middle line:84% So here, we have now for the first idea time, the notion 00:20:04.110 --> 00:20:06.930 align:middle line:84% that polypeptide chains can be covalently linked 00:20:06.930 --> 00:20:11.640 align:middle line:84% to one another through these cross-links, as indicated here. 00:20:11.640 --> 00:20:14.160 align:middle line:84% Conversely, if you add a reducing agent, 00:20:14.160 --> 00:20:16.620 align:middle line:84% that will add protons back to this 00:20:16.620 --> 00:20:20.100 align:middle line:84% and reduce the oxidation state of the sulfurs, 00:20:20.100 --> 00:20:25.560 align:middle line:84% once again causing the disulfide bond to fall apart. 00:20:25.560 --> 00:20:27.870 align:middle line:84% On principle, these disulfide bonds 00:20:27.870 --> 00:20:30.870 align:middle line:84% could be used to link two proteins together. 00:20:30.870 --> 00:20:33.270 align:middle line:84% But more often than not, if you look 00:20:33.270 --> 00:20:36.850 align:middle line:84% at the structure of a single protein protein, 00:20:36.850 --> 00:20:38.760 align:middle line:84% here's the structure of a single protein. 00:20:38.760 --> 00:20:44.800 align:middle line:84% And often, there are intramolecular bonds, 00:20:44.800 --> 00:20:49.030 align:middle line:84% disulfide bonds, i.e. bonds from one domain 00:20:49.030 --> 00:20:51.430 align:middle line:84% of the protein to another, from one part of the protein 00:20:51.430 --> 00:20:52.180 align:middle line:90% to the other. 00:20:52.180 --> 00:20:53.620 align:middle line:90% I'll draw them in right here. 00:20:53.620 --> 00:20:55.510 align:middle line:90% Here might be a disulfide bond. 00:20:55.510 --> 00:20:57.108 align:middle line:90% Here might be a disulfide bond. 00:20:57.108 --> 00:20:58.150 align:middle line:90% And I could go on and on. 00:20:58.150 --> 00:21:00.370 align:middle line:84% There might be another one over here. 00:21:00.370 --> 00:21:02.950 align:middle line:84% Why do we have these disulfide bonds? 00:21:02.950 --> 00:21:05.410 align:middle line:84% Because, as we'll indicate very shortly, 00:21:05.410 --> 00:21:07.750 align:middle line:84% the three-dimensional structure of a protein 00:21:07.750 --> 00:21:11.010 align:middle line:90% is very specifically determined. 00:21:11.010 --> 00:21:12.770 align:middle line:84% A protein can only function when it 00:21:12.770 --> 00:21:14.600 align:middle line:84% assumes a certain three-dimensional 00:21:14.600 --> 00:21:20.480 align:middle line:84% configuration, when it assumes a certain three-dimensional 00:21:20.480 --> 00:21:24.860 align:middle line:90% stereochemical configuration. 00:21:24.860 --> 00:21:27.290 align:middle line:84% When we talk about stereochemistry, 00:21:27.290 --> 00:21:29.780 align:middle line:84% we're talking about the three dimensional structures 00:21:29.780 --> 00:21:31.820 align:middle line:90% of molecules small and large. 00:21:31.820 --> 00:21:35.000 align:middle line:84% And here, we begin to touch on a theme of how 00:21:35.000 --> 00:21:39.500 align:middle line:84% these complex polypeptide chains are able to create proteins 00:21:39.500 --> 00:21:42.410 align:middle line:84% that have very specific, often very rigid 00:21:42.410 --> 00:21:44.690 align:middle line:84% structures in three-dimensional space. 00:21:44.690 --> 00:21:47.540 align:middle line:84% Part of this structural rigidity is maintained 00:21:47.540 --> 00:21:53.030 align:middle line:84% by these covalent disulfide bonds, which link, 00:21:53.030 --> 00:21:56.120 align:middle line:84% tightly link, neighboring regions, or even not so 00:21:56.120 --> 00:22:00.680 align:middle line:84% neighboring regions, of a single polypeptide chain, 00:22:00.680 --> 00:22:03.050 align:middle line:90% these intramolecular links. 00:22:03.050 --> 00:22:06.320 align:middle line:84% This doesn't preclude there being intermolecular links 00:22:06.320 --> 00:22:09.080 align:middle line:84% between two polypeptide chains that are mediated 00:22:09.080 --> 00:22:12.660 align:middle line:90% as well by the disulfide bonds. 00:22:12.660 --> 00:22:15.630 align:middle line:84% Here's another very peculiar amino acid 00:22:15.630 --> 00:22:19.710 align:middle line:84% because what you see here is that the side chain, which 00:22:19.710 --> 00:22:24.210 align:middle line:84% is CH2-CH2-CH2, is hydrogen-bonded here 00:22:24.210 --> 00:22:26.210 align:middle line:90% to the amine group. 00:22:26.210 --> 00:22:28.780 align:middle line:84% It's not swinging out in free space. 00:22:28.780 --> 00:22:29.690 align:middle line:90% I'm sorry. 00:22:29.690 --> 00:22:31.310 align:middle line:90% I misspoke. 00:22:31.310 --> 00:22:34.610 align:middle line:84% What we see here is CH2-CH2 is covalently 00:22:34.610 --> 00:22:36.080 align:middle line:90% bonded to the amine group. 00:22:36.080 --> 00:22:38.480 align:middle line:90% You picked that up, right? 00:22:38.480 --> 00:22:40.640 align:middle line:90% Whew, I was just testing you. 00:22:40.640 --> 00:22:41.420 align:middle line:90% Sure I was. 00:22:41.420 --> 00:22:41.930 align:middle line:90% OK. 00:22:41.930 --> 00:22:45.420 align:middle line:84% So here, we see a five-membered ring that's created. 00:22:45.420 --> 00:22:48.390 align:middle line:84% So here, this thing is not swinging out in free space. 00:22:48.390 --> 00:22:51.920 align:middle line:84% It creates a five-membered ring, where the end of the side chain 00:22:51.920 --> 00:22:54.680 align:middle line:84% is actually covalently linked to the amino group. 00:22:54.680 --> 00:22:57.950 align:middle line:84% And that also has implications for the structure of proteins 00:22:57.950 --> 00:23:00.620 align:middle line:84% because this particular amino acid, whenever 00:23:00.620 --> 00:23:03.480 align:middle line:84% it occurs within a polypeptide chain, 00:23:03.480 --> 00:23:06.770 align:middle line:84% doesn't have the flexibility of assuming certain configurations 00:23:06.770 --> 00:23:10.730 align:middle line:84% that the other ones have whose four side chains are not 00:23:10.730 --> 00:23:12.290 align:middle line:90% so encumbered. 00:23:12.290 --> 00:23:14.180 align:middle line:84% None of them has total flexibility. 00:23:14.180 --> 00:23:16.190 align:middle line:84% But this one is far more encumbered 00:23:16.190 --> 00:23:19.160 align:middle line:84% in the kinds of three dimensional structures 00:23:19.160 --> 00:23:21.350 align:middle line:90% that it can assume. 00:23:21.350 --> 00:23:26.060 align:middle line:84% And with that in mind, we begin to ask questions 00:23:26.060 --> 00:23:29.510 align:middle line:84% about how polypeptide chains assume 00:23:29.510 --> 00:23:31.490 align:middle line:90% three-dimensional structure. 00:23:31.490 --> 00:23:39.560 align:middle line:84% If we talk about a polypeptide chain, in our minds hopefully-- 00:23:39.560 --> 00:23:42.992 align:middle line:90% there's only 28 combinations? 00:23:42.992 --> 00:23:44.480 align:middle line:90% AUDIENCE: [INAUDIBLE]. 00:23:44.480 --> 00:23:46.250 align:middle line:84% ROBERT WEINBERG: Oh, am I good or what? 00:23:46.250 --> 00:23:48.590 align:middle line:90% OK, anyhow. 00:23:48.590 --> 00:23:50.360 align:middle line:90% All right, so look here. 00:23:50.360 --> 00:23:55.060 align:middle line:84% And here, you see this is a typical polypeptide chain. 00:23:55.060 --> 00:23:57.640 align:middle line:84% Here, we have a three-letter code. 00:23:57.640 --> 00:24:00.340 align:middle line:84% In truth, there there's a single-letter code, which 00:24:00.340 --> 00:24:02.530 align:middle line:90% was introduced around 1965. 00:24:02.530 --> 00:24:06.910 align:middle line:84% So each of the 20 amino acids has its own single-letter code. 00:24:06.910 --> 00:24:13.030 align:middle line:84% And to make a frank and depressing admission, 35 years, 00:24:13.030 --> 00:24:15.460 align:middle line:84% 40 years after the single amino acid letter 00:24:15.460 --> 00:24:19.020 align:middle line:84% code was instituted, I still haven't learned it. 00:24:19.020 --> 00:24:21.020 align:middle line:84% But we can learn these three letter codes, which 00:24:21.020 --> 00:24:23.780 align:middle line:90% fortunately are present here. 00:24:23.780 --> 00:24:27.440 align:middle line:84% In the single-letter code, L is leucine and A is art-- 00:24:27.440 --> 00:24:28.550 align:middle line:90% A is-- 00:24:28.550 --> 00:24:29.300 align:middle line:90% AUDIENCE: Alanine. 00:24:29.300 --> 00:24:31.620 align:middle line:84% ROBERT WEINBERG: See, they know it. 00:24:31.620 --> 00:24:33.140 align:middle line:84% This is another example of not being 00:24:33.140 --> 00:24:35.870 align:middle line:84% able to teach old dogs new tricks. 00:24:35.870 --> 00:24:39.420 align:middle line:84% Anyhow, so here, we see the way-- 00:24:39.420 --> 00:24:43.010 align:middle line:84% one way by which one might depict an amino acid-- 00:24:43.010 --> 00:24:45.300 align:middle line:84% an amino acid chain, a polypeptide chain. 00:24:45.300 --> 00:24:49.310 align:middle line:84% And keep in mind this can go on indefinitely. 00:24:49.310 --> 00:24:52.160 align:middle line:84% As we begin to wrestle with the three-dimensional structure 00:24:52.160 --> 00:24:54.710 align:middle line:84% of the chain, we begin to realize the following. 00:24:54.710 --> 00:24:58.790 align:middle line:84% And that is that after the chain is initially synthesized, 00:24:58.790 --> 00:25:00.710 align:middle line:90% it's initially chaotic. 00:25:00.710 --> 00:25:03.350 align:middle line:84% And as it extends, it increasingly 00:25:03.350 --> 00:25:08.690 align:middle line:84% begins to assume a very specific molecular, three-dimensional 00:25:08.690 --> 00:25:11.490 align:middle line:84% molecular configuration, which is indicated down here. 00:25:11.490 --> 00:25:14.960 align:middle line:84% So the chaos that operates initially 00:25:14.960 --> 00:25:19.800 align:middle line:84% will eventually result in a native configuration over here, 00:25:19.800 --> 00:25:22.220 align:middle line:84% which, in many respects, often represents 00:25:22.220 --> 00:25:24.860 align:middle line:90% the lowest free energy state. 00:25:24.860 --> 00:25:26.677 align:middle line:84% Since, for the last 40 years, people 00:25:26.677 --> 00:25:28.760 align:middle line:84% have been able to have been trying to figure out-- 00:25:28.760 --> 00:25:30.680 align:middle line:84% if you knew the amino acid sequence 00:25:30.680 --> 00:25:32.930 align:middle line:84% of this primary polypeptide here, 00:25:32.930 --> 00:25:35.390 align:middle line:84% if you knew its primary structure-- 00:25:35.390 --> 00:25:37.910 align:middle line:84% and when I say primary structure, what I mean 00:25:37.910 --> 00:25:39.987 align:middle line:84% is the subsequence of the amino acids. 00:25:39.987 --> 00:25:42.320 align:middle line:84% So if you knew the primary structure of the amino acids, 00:25:42.320 --> 00:25:45.890 align:middle line:84% you should, in principle, be able to develop a computer 00:25:45.890 --> 00:25:48.320 align:middle line:84% algorithm that would predict the three-dimensional 00:25:48.320 --> 00:25:51.560 align:middle line:84% configuration, which is shown here in a very schematic way, 00:25:51.560 --> 00:25:54.710 align:middle line:84% and which we'll discuss in much greater detail shortly. 00:25:54.710 --> 00:25:57.620 align:middle line:84% And the fact is, after 40 years of trying, 00:25:57.620 --> 00:26:00.470 align:middle line:84% one still is unable to do that, i.e. 00:26:00.470 --> 00:26:04.220 align:middle line:84% if I were to give the primary amino acid 00:26:04.220 --> 00:26:07.340 align:middle line:84% sequence of a polypeptide to the smartest 00:26:07.340 --> 00:26:08.790 align:middle line:90% biochemist in the world-- 00:26:08.790 --> 00:26:10.610 align:middle line:84% and there are some very smart ones-- 00:26:10.610 --> 00:26:12.620 align:middle line:84% he or she could still not tell me 00:26:12.620 --> 00:26:15.110 align:middle line:84% what the three-dimensional structure of this protein 00:26:15.110 --> 00:26:18.170 align:middle line:90% with total certainly would be. 00:26:18.170 --> 00:26:18.800 align:middle line:90% Why? 00:26:18.800 --> 00:26:21.380 align:middle line:84% Because there's an almost infinite number 00:26:21.380 --> 00:26:24.720 align:middle line:84% of intramolecular interactions that greatly 00:26:24.720 --> 00:26:29.740 align:middle line:84% complicate how the protein assumes this structure. 00:26:29.740 --> 00:26:32.560 align:middle line:84% Moreover, if we talk of this as the native state 00:26:32.560 --> 00:26:34.960 align:middle line:84% of the protein, we can imagine that there's 00:26:34.960 --> 00:26:38.080 align:middle line:84% ways of disrupting that because much of this native state 00:26:38.080 --> 00:26:42.260 align:middle line:84% is created by intramolecular hydrogen bonds. 00:26:42.260 --> 00:26:44.840 align:middle line:84% Remember, the hydrogen bonds are relatively weak. 00:26:44.840 --> 00:26:48.970 align:middle line:84% And if we heat up the temperature, 00:26:48.970 --> 00:26:50.950 align:middle line:84% then we can break hydrogen bonds. 00:26:50.950 --> 00:26:55.760 align:middle line:84% And therefore, every time we fry an egg, for example, 00:26:55.760 --> 00:26:58.330 align:middle line:84% if we want to get down to Earth, we denature. 00:26:58.330 --> 00:26:59.965 align:middle line:84% We break up the three-dimensional, 00:26:59.965 --> 00:27:02.050 align:middle line:84% the native three-dimensional structure 00:27:02.050 --> 00:27:05.260 align:middle line:84% of the albumin molecules that constitute the egg white. 00:27:05.260 --> 00:27:07.630 align:middle line:84% And so when everything turns white, what we've done 00:27:07.630 --> 00:27:10.900 align:middle line:84% is to take a native molecule like this, heated it 00:27:10.900 --> 00:27:14.590 align:middle line:84% up to temperatures where the intramolecular bonds no 00:27:14.590 --> 00:27:17.740 align:middle line:84% longer stabilize-- notably, hydrogen bonds no longer 00:27:17.740 --> 00:27:20.170 align:middle line:84% stabilize this three dimensional configuration. 00:27:20.170 --> 00:27:23.530 align:middle line:84% And we put it into a denatured state, which 00:27:23.530 --> 00:27:26.250 align:middle line:90% might be all the way up here. 00:27:26.250 --> 00:27:30.990 align:middle line:84% And therefore, this acquisition of a native configuration 00:27:30.990 --> 00:27:36.060 align:middle line:84% or a native state, native representing the natural state, 00:27:36.060 --> 00:27:38.880 align:middle line:84% is also reversible in many molecules 00:27:38.880 --> 00:27:40.530 align:middle line:90% simply by heating them up. 00:27:40.530 --> 00:27:43.140 align:middle line:84% There are, to be sure, yet other molecules which are different 00:27:43.140 --> 00:27:45.990 align:middle line:84% from egg white, from the albumin in egg white, where 00:27:45.990 --> 00:27:49.590 align:middle line:84% if you cool them back down, they'll spontaneously reassume 00:27:49.590 --> 00:27:50.820 align:middle line:90% their native structure. 00:27:50.820 --> 00:27:54.810 align:middle line:84% Many proteins, most, will not do so. 00:27:54.810 --> 00:27:56.400 align:middle line:84% Again, let's go back to this issue 00:27:56.400 --> 00:27:59.650 align:middle line:84% of the acquisition of complex three-dimensional structures. 00:27:59.650 --> 00:28:04.620 align:middle line:84% And here, we begin to see how some of this structure 00:28:04.620 --> 00:28:08.700 align:middle line:84% is acquired and stabilized through these intramolecular 00:28:08.700 --> 00:28:09.810 align:middle line:90% hydrogen bonds. 00:28:09.810 --> 00:28:12.690 align:middle line:84% And there are many opportunities for these intramolecular 00:28:12.690 --> 00:28:15.750 align:middle line:84% hydrogen bonds because here we see one polypeptide chain, 00:28:15.750 --> 00:28:17.140 align:middle line:90% here we see another. 00:28:17.140 --> 00:28:20.340 align:middle line:84% And we see that the NH2 group right here-- 00:28:20.340 --> 00:28:23.760 align:middle line:84% I'm sorry, the nitrogen group here with the proton side 00:28:23.760 --> 00:28:27.580 align:middle line:84% chain and the carbonyl group here with the oxygen 00:28:27.580 --> 00:28:28.840 align:middle line:90% are not encumbered. 00:28:28.840 --> 00:28:31.540 align:middle line:84% They are, in principle, available to form 00:28:31.540 --> 00:28:34.630 align:middle line:84% hydrogen bonds with a polypeptide chain 00:28:34.630 --> 00:28:35.770 align:middle line:90% somewhere else. 00:28:35.770 --> 00:28:37.900 align:middle line:84% Now, this other polypeptide chain 00:28:37.900 --> 00:28:39.880 align:middle line:84% could, once again, be from another protein, 00:28:39.880 --> 00:28:41.750 align:middle line:90% from another polypeptide. 00:28:41.750 --> 00:28:44.410 align:middle line:84% But more often than not, we're, once again, 00:28:44.410 --> 00:28:49.150 align:middle line:84% dealing with intramolecular cross-links. 00:28:49.150 --> 00:28:51.370 align:middle line:84% But in this case, the intramolecular cross-links 00:28:51.370 --> 00:28:54.850 align:middle line:84% are not disulfide bonds, which are covalent and hard, 00:28:54.850 --> 00:28:57.970 align:middle line:84% stable as a rock in the absence of reducing agents. 00:28:57.970 --> 00:29:01.120 align:middle line:84% Here, we're talking about much weaker bonds, hydrogen bonds, 00:29:01.120 --> 00:29:07.180 align:middle line:84% which also act between different loops of the protein 00:29:07.180 --> 00:29:09.910 align:middle line:84% and serve, once again, to stabilize 00:29:09.910 --> 00:29:12.550 align:middle line:84% the three-dimensional structure, the native state 00:29:12.550 --> 00:29:14.060 align:middle line:90% of the protein. 00:29:14.060 --> 00:29:16.900 align:middle line:84% And you can see how these opportunities for forming 00:29:16.900 --> 00:29:20.260 align:middle line:84% multiple hydrogen bonds can create an enormous degree 00:29:20.260 --> 00:29:22.600 align:middle line:90% of stability. 00:29:22.600 --> 00:29:25.750 align:middle line:84% And here are some examples of what we now 00:29:25.750 --> 00:29:29.230 align:middle line:84% call the secondary structure of the protein. 00:29:29.230 --> 00:29:32.560 align:middle line:84% Just a second ago, or several minutes ago to be honest-- 00:29:32.560 --> 00:29:36.040 align:middle line:84% and I'm always honest with you, class-- 00:29:36.040 --> 00:29:38.860 align:middle line:84% the primary structure is the amino acid sequence. 00:29:38.860 --> 00:29:41.110 align:middle line:84% The secondary structure represents 00:29:41.110 --> 00:29:42.670 align:middle line:90% configurations like this. 00:29:42.670 --> 00:29:44.890 align:middle line:90% Here is an alpha helix. 00:29:44.890 --> 00:29:49.150 align:middle line:84% And here is a beta pleated sheet. 00:29:49.150 --> 00:29:51.250 align:middle line:84% And what we see here in this alpha helix 00:29:51.250 --> 00:29:53.770 align:middle line:84% is we have a helical structure where 00:29:53.770 --> 00:29:56.650 align:middle line:84% the amine group down here, the hydrogen 00:29:56.650 --> 00:29:59.050 align:middle line:84% bonds with a residue, which is, I think, 00:29:59.050 --> 00:30:00.970 align:middle line:90% 3 and 1/2 residues upstream-- 00:30:00.970 --> 00:30:04.780 align:middle line:84% 1, 2-- there's an amine down there-- so 00:30:04.780 --> 00:30:08.270 align:middle line:84% with a carbonyl group that's 3 and 1/2 residues upstream 00:30:08.270 --> 00:30:08.770 align:middle line:90% of it. 00:30:08.770 --> 00:30:12.910 align:middle line:84% This one, once again, reaches 3 and 1/2 residues upstream. 00:30:12.910 --> 00:30:16.030 align:middle line:84% Not all the hydrogen bonds are shown in the background. 00:30:16.030 --> 00:30:18.510 align:middle line:84% Only the ones on our side of the helix 00:30:18.510 --> 00:30:20.260 align:middle line:84% are shown, on the front side of the helix. 00:30:20.260 --> 00:30:23.350 align:middle line:84% But you can imagine that this can perpetuate itself. 00:30:23.350 --> 00:30:27.520 align:middle line:84% And each of these carbonyls may associate with a proton 00:30:27.520 --> 00:30:31.540 align:middle line:84% from an NH group that's either above or below that particular 00:30:31.540 --> 00:30:32.240 align:middle line:90% residue. 00:30:32.240 --> 00:30:35.320 align:middle line:84% And this, in turn, can create a helical structure. 00:30:35.320 --> 00:30:39.550 align:middle line:84% By the way, proline doesn't fit well in this. 00:30:39.550 --> 00:30:41.800 align:middle line:84% If you add a proline in here, proline 00:30:41.800 --> 00:30:45.440 align:middle line:84% is known in the trade as a helix breaker. 00:30:45.440 --> 00:30:45.940 align:middle line:90% Why? 00:30:45.940 --> 00:30:49.750 align:middle line:84% Because it cannot twist itself around to form an alpha helix. 00:30:49.750 --> 00:30:52.180 align:middle line:84% And so if the primary amino acid were 00:30:52.180 --> 00:30:54.850 align:middle line:84% to dictate that a proline would be inserted right 00:30:54.850 --> 00:30:57.250 align:middle line:84% here, for example, then this helix 00:30:57.250 --> 00:31:00.010 align:middle line:84% might exist down below and up above. 00:31:00.010 --> 00:31:02.710 align:middle line:84% But it would not be continuous because the presence 00:31:02.710 --> 00:31:06.010 align:middle line:84% of a proline is highly disruptive of the formation 00:31:06.010 --> 00:31:09.260 align:middle line:90% of an alpha helix. 00:31:09.260 --> 00:31:10.720 align:middle line:84% This means that, in principle, you 00:31:10.720 --> 00:31:13.480 align:middle line:84% can make some predictions about the localized 00:31:13.480 --> 00:31:16.600 align:middle line:84% structure of a polypeptide by knowing whether or not proline 00:31:16.600 --> 00:31:18.010 align:middle line:90% is present, for example. 00:31:18.010 --> 00:31:19.990 align:middle line:84% But that still doesn't give you the power 00:31:19.990 --> 00:31:22.750 align:middle line:84% to predict the entire three dimensional structure 00:31:22.750 --> 00:31:25.490 align:middle line:90% of the finished protein itself. 00:31:25.490 --> 00:31:29.080 align:middle line:84% Now, let's agree that this is the secondary structure 00:31:29.080 --> 00:31:31.420 align:middle line:84% of the protein, i.e. the various domains 00:31:31.420 --> 00:31:34.870 align:middle line:84% which often form alpha helices within a certain segment 00:31:34.870 --> 00:31:35.830 align:middle line:90% of the protein. 00:31:35.830 --> 00:31:37.930 align:middle line:84% Or a certain segment of the protein 00:31:37.930 --> 00:31:39.610 align:middle line:90% will form beta pleated sheets. 00:31:39.610 --> 00:31:42.160 align:middle line:84% And there are several or several other less common kinds 00:31:42.160 --> 00:31:44.720 align:middle line:90% of secondary structure. 00:31:44.720 --> 00:31:48.310 align:middle line:84% And here, we deal with tertiary structure. 00:31:48.310 --> 00:31:50.260 align:middle line:84% Now, we're getting really interesting. 00:31:50.260 --> 00:31:51.730 align:middle line:90% Or maybe you don't like it. 00:31:51.730 --> 00:31:54.190 align:middle line:84% But some people say it's really interesting 00:31:54.190 --> 00:31:57.640 align:middle line:84% because here are the tertiary structures of some arbitrarily 00:31:57.640 --> 00:31:59.680 align:middle line:90% chosen proteins. 00:31:59.680 --> 00:32:05.350 align:middle line:84% Here, the tertiary structure of this particular protein-- 00:32:05.350 --> 00:32:08.950 align:middle line:84% and the identities of these are not given in our textbook. 00:32:08.950 --> 00:32:10.785 align:middle line:84% And I'm sure if we spent two or three weeks, 00:32:10.785 --> 00:32:12.160 align:middle line:84% we could find out what they were. 00:32:12.160 --> 00:32:15.940 align:middle line:84% But anyhow, here is a protein, a three-dimensional structure 00:32:15.940 --> 00:32:20.980 align:middle line:84% of a protein, which is composed of four alpha helices, which 00:32:20.980 --> 00:32:26.570 align:middle line:84% go up, another alpha helix, alpha helix, alpha helix, alpha 00:32:26.570 --> 00:32:27.170 align:middle line:90% helix. 00:32:27.170 --> 00:32:28.760 align:middle line:84% They're depicted here, fortunately, 00:32:28.760 --> 00:32:30.600 align:middle line:90% in four different colors. 00:32:30.600 --> 00:32:33.350 align:middle line:84% And so we see that when we talk about tertiary structure, 00:32:33.350 --> 00:32:37.130 align:middle line:84% we're talking about how the alpha helices are disposed 00:32:37.130 --> 00:32:39.010 align:middle line:90% with respect to one another. 00:32:39.010 --> 00:32:41.110 align:middle line:84% The primary structure is the amino acid sequence 00:32:41.110 --> 00:32:42.290 align:middle line:90% is not shown here. 00:32:42.290 --> 00:32:44.110 align:middle line:84% The secondary structure represents 00:32:44.110 --> 00:32:46.450 align:middle line:90% these individual alpha helices. 00:32:46.450 --> 00:32:48.640 align:middle line:84% And the tertiary structure represents 00:32:48.640 --> 00:32:51.620 align:middle line:84% how these alpha helices are arranged vis a vis one another. 00:32:51.620 --> 00:32:57.320 align:middle line:84% Here is a protein which is structured much differently. 00:32:57.320 --> 00:33:02.360 align:middle line:84% Here, this is formed of many beta pleated sheets. 00:33:02.360 --> 00:33:05.180 align:middle line:84% We saw them in the last figure, in the last overhead. 00:33:05.180 --> 00:33:08.360 align:middle line:84% You see it has a quite different overall three dimensional 00:33:08.360 --> 00:33:09.660 align:middle line:90% structure. 00:33:09.660 --> 00:33:11.460 align:middle line:84% This could be the beginning of an alpha 00:33:11.460 --> 00:33:14.460 align:middle line:84% helix down here, although that's quite equivocal. 00:33:14.460 --> 00:33:16.230 align:middle line:84% And here, we see yet another point. 00:33:16.230 --> 00:33:19.260 align:middle line:84% And that is, as we said before, the tertiary structure 00:33:19.260 --> 00:33:21.930 align:middle line:84% independent of these alpha and beta-- 00:33:21.930 --> 00:33:23.640 align:middle line:84% alpha helices and beta pleated sheets 00:33:23.640 --> 00:33:28.080 align:middle line:84% may be stabilized by these covalent interstrand 00:33:28.080 --> 00:33:31.440 align:middle line:84% cross-linnks formed by the cysteines. 00:33:31.440 --> 00:33:33.910 align:middle line:84% And in the end, if we put all that together, 00:33:33.910 --> 00:33:36.390 align:middle line:84% then we come to the realization that the three dimensional 00:33:36.390 --> 00:33:39.780 align:middle line:84% structure of a protein, as determined by the art 00:33:39.780 --> 00:33:40.350 align:middle line:90% of X-ray-- 00:33:40.350 --> 00:33:45.140 align:middle line:90% 00:33:45.140 --> 00:33:47.120 align:middle line:90% there we go. 00:33:47.120 --> 00:33:49.920 align:middle line:90% I'm not actually dyslexic. 00:33:49.920 --> 00:33:52.285 align:middle line:84% I actually have a cousin who I won't mention 00:33:52.285 --> 00:33:54.660 align:middle line:84% whose son was so dyslexic that when he came to stairways, 00:33:54.660 --> 00:33:56.820 align:middle line:84% he didn't know whether to put his foot up or down. 00:33:56.820 --> 00:33:58.090 align:middle line:90% Now, that's difficulty. 00:33:58.090 --> 00:34:00.680 align:middle line:90% This is-- this is not so bad-- 00:34:00.680 --> 00:34:03.840 align:middle line:84% OK, anyhow-- because I solved it within less than two minutes 00:34:03.840 --> 00:34:04.340 align:middle line:90% time. 00:34:04.340 --> 00:34:04.700 align:middle line:90% All right. 00:34:04.700 --> 00:34:07.310 align:middle line:84% So here, we see this is what the three-dimensional structure 00:34:07.310 --> 00:34:08.510 align:middle line:90% of a protein looks like. 00:34:08.510 --> 00:34:10.670 align:middle line:84% This is called a space-filling model 00:34:10.670 --> 00:34:13.010 align:middle line:84% because here one draws in, as determined 00:34:13.010 --> 00:34:16.699 align:middle line:84% by X-ray crystallography, if we could see what a protein looks 00:34:16.699 --> 00:34:21.530 align:middle line:84% like, what it actually must look like, where each of the atoms, 00:34:21.530 --> 00:34:24.050 align:middle line:84% including these side chains, is actually depicted. 00:34:24.050 --> 00:34:28.852 align:middle line:84% Before, when we used these far more schematic descriptions 00:34:28.852 --> 00:34:31.310 align:middle line:84% like here, we were just talking about the overall structure 00:34:31.310 --> 00:34:31.977 align:middle line:90% of the backbone. 00:34:31.977 --> 00:34:35.719 align:middle line:84% We weren't really indicating where the side chains were 00:34:35.719 --> 00:34:37.718 align:middle line:84% and what space they would fill up. 00:34:37.718 --> 00:34:39.260 align:middle line:84% And if we give them the chance, if we 00:34:39.260 --> 00:34:42.199 align:middle line:84% put in all of the other atoms, the side chains, 00:34:42.199 --> 00:34:45.739 align:middle line:84% and we create a space-filling model where 00:34:45.739 --> 00:34:48.590 align:middle line:84% the actual atoms are shown, this is what 00:34:48.590 --> 00:34:50.159 align:middle line:90% the protein would look like. 00:34:50.159 --> 00:34:53.300 align:middle line:84% And the fact of the matter is that virtually all proteins 00:34:53.300 --> 00:34:55.800 align:middle line:90% have very specific structures. 00:34:55.800 --> 00:34:58.580 align:middle line:84% It's not as if they can shift from one structure to another. 00:34:58.580 --> 00:35:01.230 align:middle line:84% Once they leave their normal native structure, 00:35:01.230 --> 00:35:07.720 align:middle line:84% they will lose their ability to do what their normal jobs are. 00:35:07.720 --> 00:35:11.020 align:middle line:84% And this particular overhead happens 00:35:11.020 --> 00:35:12.700 align:middle line:84% to bring in yet another theme that we're 00:35:12.700 --> 00:35:16.000 align:middle line:84% going to focus on increasingly, which is, what do proteins 00:35:16.000 --> 00:35:17.590 align:middle line:90% do in cells? 00:35:17.590 --> 00:35:19.090 align:middle line:90% I'm glad I asked that question. 00:35:19.090 --> 00:35:23.380 align:middle line:84% One of the things they do is they act as catalysts, i.e. 00:35:23.380 --> 00:35:25.060 align:middle line:90% as enzymes. 00:35:25.060 --> 00:35:28.390 align:middle line:84% The fact is, as we'll discuss later, 00:35:28.390 --> 00:35:30.730 align:middle line:84% virtually all biochemical reactions 00:35:30.730 --> 00:35:35.380 align:middle line:84% require an enzyme catalyst in order to propel them forward. 00:35:35.380 --> 00:35:37.960 align:middle line:84% That is to say, if there's a biochemical reaction 00:35:37.960 --> 00:35:41.920 align:middle line:84% to occur, almost always, it will not occur spontaneously, 00:35:41.920 --> 00:35:44.380 align:middle line:84% the same way that a hydroxyl ion and a hydrogen 00:35:44.380 --> 00:35:46.780 align:middle line:84% will join together spontaneously in water. 00:35:46.780 --> 00:35:50.830 align:middle line:84% Almost all biochemical reactions require the mediation 00:35:50.830 --> 00:35:56.600 align:middle line:84% of an enzyme, which is a biological catalyst, in order 00:35:56.600 --> 00:35:59.630 align:middle line:90% to encourage this to happen. 00:35:59.630 --> 00:36:05.840 align:middle line:84% And almost all catalysts in our cells are proteins. 00:36:05.840 --> 00:36:11.830 align:middle line:84% So if you have 4,326 distinct biochemical reactions occurring 00:36:11.830 --> 00:36:14.230 align:middle line:84% in the cell, that means that there's probably 00:36:14.230 --> 00:36:16.870 align:middle line:84% almost as many distinct enzymes, each one of which 00:36:16.870 --> 00:36:19.780 align:middle line:84% is assigned to mediate one or another 00:36:19.780 --> 00:36:22.760 align:middle line:84% of those distinct biochemical reactions. 00:36:22.760 --> 00:36:24.230 align:middle line:90% And here, we see the fact-- 00:36:24.230 --> 00:36:28.540 align:middle line:84% this is an enzyme which happens to be called hexokinase. 00:36:28.540 --> 00:36:31.180 align:middle line:84% Recall that the -ase suffix at the end 00:36:31.180 --> 00:36:34.090 align:middle line:84% dictates that this is already an enzyme rather 00:36:34.090 --> 00:36:35.650 align:middle line:90% than a carbohydrate. 00:36:35.650 --> 00:36:40.930 align:middle line:84% And this attaches, in fact, a phosphate group onto glucose. 00:36:40.930 --> 00:36:43.840 align:middle line:84% And what happens is that the glucose, which 00:36:43.840 --> 00:36:47.140 align:middle line:84% is the substrate which is acted upon by the catalyst, 00:36:47.140 --> 00:36:51.370 align:middle line:84% is pulled into this site in the protein, which 00:36:51.370 --> 00:36:56.520 align:middle line:84% is highly specialized to mediate the enzymatic reaction. 00:36:56.520 --> 00:36:59.340 align:middle line:84% Almost all of the business of this complex enzyme 00:36:59.340 --> 00:37:01.650 align:middle line:90% is carried out right here. 00:37:01.650 --> 00:37:04.230 align:middle line:84% And somehow, a lot of the other amino acids 00:37:04.230 --> 00:37:06.930 align:middle line:84% that are located at a distance are doing other things, 00:37:06.930 --> 00:37:09.780 align:middle line:84% like regulating the activity of the enzyme. 00:37:09.780 --> 00:37:11.730 align:middle line:84% But the actual business end of the enzyme 00:37:11.730 --> 00:37:16.740 align:middle line:84% is present in what is called a catalytic cleft, an active site 00:37:16.740 --> 00:37:19.410 align:middle line:84% of this enzyme, in which the substrates are pulled in 00:37:19.410 --> 00:37:23.670 align:middle line:84% and are manipulated and changed chemically by the actions 00:37:23.670 --> 00:37:26.220 align:middle line:90% of this particular enzyme. 00:37:26.220 --> 00:37:31.230 align:middle line:84% Now, in saying that virtually all catalysts, but not all, are 00:37:31.230 --> 00:37:35.090 align:middle line:84% proteins, I also mean to say that proteins 00:37:35.090 --> 00:37:37.920 align:middle line:84% have a second major function in the body. 00:37:37.920 --> 00:37:40.850 align:middle line:84% The first major function is to act as enzymes and catalysts. 00:37:40.850 --> 00:37:45.710 align:middle line:84% The second major function is to create biochemical structures, 00:37:45.710 --> 00:37:46.460 align:middle line:90% i.e. 00:37:46.460 --> 00:37:49.160 align:middle line:84% structures of different cytoskeleton proteins, 00:37:49.160 --> 00:37:53.460 align:middle line:84% such as I showed you two lectures ago. 00:37:53.460 --> 00:37:56.690 align:middle line:84% And so we're going to come repeatedly to situations where 00:37:56.690 --> 00:37:59.150 align:middle line:84% complex structural entities in the cell 00:37:59.150 --> 00:38:02.510 align:middle line:84% are composed of different structural proteins. 00:38:02.510 --> 00:38:04.610 align:middle line:84% Again, this is just a prelude to talking 00:38:04.610 --> 00:38:06.170 align:middle line:90% about these in greater detail. 00:38:06.170 --> 00:38:08.060 align:middle line:90% These two major functions-- 00:38:08.060 --> 00:38:09.920 align:middle line:84% enzymatic catalysis on the one hand 00:38:09.920 --> 00:38:13.110 align:middle line:84% and creating structure on the other. 00:38:13.110 --> 00:38:17.330 align:middle line:84% And so now, we get to really four hierarchical levels 00:38:17.330 --> 00:38:19.100 align:middle line:90% of protein structure. 00:38:19.100 --> 00:38:22.222 align:middle line:90% 00:38:22.222 --> 00:38:25.860 align:middle line:84% The primary structure is the amino acid sequence. 00:38:25.860 --> 00:38:29.150 align:middle line:84% And if we dwell for a second on this amino acid sequence, 00:38:29.150 --> 00:38:32.300 align:middle line:84% let's realize that any single amino acid can 00:38:32.300 --> 00:38:34.230 align:middle line:90% follow any other amino acid. 00:38:34.230 --> 00:38:36.890 align:middle line:84% So what that means is that if glycine 00:38:36.890 --> 00:38:39.380 align:middle line:84% is the first amino acid, as it happens to be here, 00:38:39.380 --> 00:38:42.290 align:middle line:84% serine is only one of 20 different possible 00:38:42.290 --> 00:38:44.960 align:middle line:90% second amino acids. 00:38:44.960 --> 00:38:51.050 align:middle line:84% Aspartic acid is only one of 20 different third amino acids, 00:38:51.050 --> 00:38:52.820 align:middle line:90% as the third residue. 00:38:52.820 --> 00:38:54.740 align:middle line:84% We often call these different residues-- 00:38:54.740 --> 00:38:57.260 align:middle line:84% the first residue, the second residue, third residue, 00:38:57.260 --> 00:38:59.400 align:middle line:84% fourth residue, and forth-- and so forth. 00:38:59.400 --> 00:39:02.570 align:middle line:84% And keep in mind, if we think about the combinatorial 00:39:02.570 --> 00:39:05.870 align:middle line:84% implications of that, the first amino acid residue 00:39:05.870 --> 00:39:07.100 align:middle line:90% can have 20 different ones. 00:39:07.100 --> 00:39:09.178 align:middle line:84% The second can have 20 different identities. 00:39:09.178 --> 00:39:10.970 align:middle line:84% The third can have 20 different identities. 00:39:10.970 --> 00:39:15.830 align:middle line:84% That means, if we make a tripeptide-- 00:39:15.830 --> 00:39:18.560 align:middle line:84% a tripeptide has three amino acids in it. 00:39:18.560 --> 00:39:22.040 align:middle line:84% That means we can make 400 dipeptides, 400 00:39:22.040 --> 00:39:24.920 align:middle line:90% distinct dipeptides. 00:39:24.920 --> 00:39:29.730 align:middle line:84% And we can make 8,000 distinct tripeptides. 00:39:29.730 --> 00:39:35.220 align:middle line:84% Now, if you imagine that the average amino acid-- 00:39:35.220 --> 00:39:38.700 align:middle line:84% the average protein in a cell is, let's say, 150 amino acid 00:39:38.700 --> 00:39:39.990 align:middle line:90% residues long. 00:39:39.990 --> 00:39:42.060 align:middle line:84% That means that, in principle, one 00:39:42.060 --> 00:39:51.510 align:middle line:84% could make 20 to the 150th power distinct amino acid sequences 00:39:51.510 --> 00:39:53.580 align:middle line:84% because of these absence of any constraints 00:39:53.580 --> 00:39:57.280 align:middle line:84% of which amino acid will follow which other amino acids. 00:39:57.280 --> 00:40:01.830 align:middle line:84% In other words, if the average polypeptide 00:40:01.830 --> 00:40:03.810 align:middle line:84% has this many residues, this is the number 00:40:03.810 --> 00:40:07.260 align:middle line:84% of distinct 150 amino acid residue-long proteins 00:40:07.260 --> 00:40:10.170 align:middle line:84% that one could, in principle, synthesize. 00:40:10.170 --> 00:40:11.670 align:middle line:84% I'm not saying all of them have ever 00:40:11.670 --> 00:40:14.400 align:middle line:84% been synthesized since the formation of life 00:40:14.400 --> 00:40:15.240 align:middle line:90% on this planet. 00:40:15.240 --> 00:40:19.260 align:middle line:84% Indeed, since some amino acid chains 00:40:19.260 --> 00:40:25.020 align:middle line:84% are 400, 500, 600, even 2,000 amino acid residues long-- 00:40:25.020 --> 00:40:27.480 align:middle line:84% I think the one that is affected in muscular dystrophy 00:40:27.480 --> 00:40:30.130 align:middle line:84% is more than 2,000 amino acids, dystrophin. 00:40:30.130 --> 00:40:31.270 align:middle line:90% Does anybody know here? 00:40:31.270 --> 00:40:32.380 align:middle line:90% It's big. 00:40:32.380 --> 00:40:35.320 align:middle line:84% Anyhow, imagine the number of possibilities. 00:40:35.320 --> 00:40:38.470 align:middle line:84% So combinatorially, life can make almost 00:40:38.470 --> 00:40:42.970 align:middle line:84% whatever types of amino acids it would like by dictating 00:40:42.970 --> 00:40:44.600 align:middle line:90% the sequence of amino acids. 00:40:44.600 --> 00:40:48.430 align:middle line:84% Now, let's just go and look here again. 00:40:48.430 --> 00:40:49.900 align:middle line:90% There's a secondary structure. 00:40:49.900 --> 00:40:52.000 align:middle line:84% The tertiary structure is the way 00:40:52.000 --> 00:40:54.640 align:middle line:84% in which the different alpha helices here 00:40:54.640 --> 00:40:57.490 align:middle line:84% or beta pleated sheets are disposed three dimensionally 00:40:57.490 --> 00:40:59.180 align:middle line:90% with respect to one another. 00:40:59.180 --> 00:41:02.530 align:middle line:84% And the quaternary structure represents 00:41:02.530 --> 00:41:06.580 align:middle line:84% how different single polypeptides are associated one 00:41:06.580 --> 00:41:07.490 align:middle line:90% with the other. 00:41:07.490 --> 00:41:11.140 align:middle line:84% So for example, hemoglobin is a tetramer. 00:41:11.140 --> 00:41:14.530 align:middle line:84% Hemoglobin doesn't exist as a monomeric protein in solution. 00:41:14.530 --> 00:41:15.610 align:middle line:90% It exists as a tetramer. 00:41:15.610 --> 00:41:18.280 align:middle line:84% And there's two kinds of globin chains. 00:41:18.280 --> 00:41:21.650 align:middle line:84% There's an alpha kind and a beta kind. 00:41:21.650 --> 00:41:24.220 align:middle line:84% And if we look in a very rough and schematic way at the way 00:41:24.220 --> 00:41:26.770 align:middle line:84% that a hemoglobin tetramer is arranged, 00:41:26.770 --> 00:41:30.490 align:middle line:84% there are two alpha polypeptide chains and two beta polypeptide 00:41:30.490 --> 00:41:31.180 align:middle line:90% chains. 00:41:31.180 --> 00:41:33.790 align:middle line:84% They're not covalently attached to one another. 00:41:33.790 --> 00:41:36.280 align:middle line:84% They're associated with one another via hydrogen bonds 00:41:36.280 --> 00:41:38.110 align:middle line:90% and hydrophobic interactions. 00:41:38.110 --> 00:41:41.830 align:middle line:84% And this is the actual native configuration of globin, 00:41:41.830 --> 00:41:43.990 align:middle line:90% two alpha and two beta chains. 00:41:43.990 --> 00:41:46.770 align:middle line:84% It doesn't exist as a single amino acid in solution. 00:41:46.770 --> 00:41:48.260 align:middle line:90% It exists as a tetramer. 00:41:48.260 --> 00:41:50.420 align:middle line:84% And indeed, most-- or I shouldn't 00:41:50.420 --> 00:41:52.490 align:middle line:84% say most-- but very many proteins exist 00:41:52.490 --> 00:41:58.250 align:middle line:84% in these configurations, where the tertiary structure 00:41:58.250 --> 00:42:02.720 align:middle line:84% represents four different amino acid chains. 00:42:02.720 --> 00:42:04.790 align:middle line:84% Each of these has an N and C-terminal. 00:42:04.790 --> 00:42:06.890 align:middle line:84% Each of these is chemically distinct. 00:42:06.890 --> 00:42:09.950 align:middle line:84% These four could probably be taken apart from one another 00:42:09.950 --> 00:42:11.930 align:middle line:84% simply by raising the temperature. 00:42:11.930 --> 00:42:13.760 align:middle line:90% And they associate like this. 00:42:13.760 --> 00:42:15.892 align:middle line:84% And in the absence of this association, 00:42:15.892 --> 00:42:18.350 align:middle line:84% if you just had one of these alphas and one of these betas, 00:42:18.350 --> 00:42:20.250 align:middle line:84% it wouldn't function well at all. 00:42:20.250 --> 00:42:23.480 align:middle line:84% In fact, it might be totally dysfunctional. 00:42:23.480 --> 00:42:26.390 align:middle line:84% One other thing that may be implicit to you, 00:42:26.390 --> 00:42:29.180 align:middle line:84% but I haven't said, but that is very important to realize, 00:42:29.180 --> 00:42:30.750 align:middle line:90% is the following. 00:42:30.750 --> 00:42:33.440 align:middle line:84% Let's imagine that this is the three-dimensional structure 00:42:33.440 --> 00:42:36.040 align:middle line:90% of a protein, as it may well be. 00:42:36.040 --> 00:42:39.940 align:middle line:84% Let's now think about hydrophobic and hydrophilic 00:42:39.940 --> 00:42:41.580 align:middle line:90% amino acids. 00:42:41.580 --> 00:42:44.730 align:middle line:84% The hydrophobic amino acids hate to be present in water. 00:42:44.730 --> 00:42:48.210 align:middle line:84% And therefore, they are, we can imagine, in this case 00:42:48.210 --> 00:42:53.460 align:middle line:84% correctly, tucked away inside the interstices of the protein 00:42:53.460 --> 00:42:55.910 align:middle line:90% far away from the surface. 00:42:55.910 --> 00:42:58.130 align:middle line:84% They don't have any contact with water. 00:42:58.130 --> 00:43:02.000 align:middle line:84% Conversely, the highly charged hydrophilic amino acids 00:43:02.000 --> 00:43:05.000 align:middle line:84% are actually sticking out at the surface. 00:43:05.000 --> 00:43:08.240 align:middle line:84% And this begins to yield yet another insight 00:43:08.240 --> 00:43:11.690 align:middle line:84% into how the three-dimensional stereochemistry of proteins 00:43:11.690 --> 00:43:15.410 align:middle line:84% is maintained and dictated because the hydrophobic amino 00:43:15.410 --> 00:43:17.840 align:middle line:84% acids, through hydrophobic interactions, 00:43:17.840 --> 00:43:20.510 align:middle line:84% stabilize the inner core of the protein that 00:43:20.510 --> 00:43:23.570 align:middle line:84% is well-shielded from the aqueous solvent. 00:43:23.570 --> 00:43:26.030 align:middle line:84% The hydrophilic amino acids are on the outside. 00:43:26.030 --> 00:43:29.340 align:middle line:84% They like to be in intimate contact with the water. 00:43:29.340 --> 00:43:31.790 align:middle line:84% So we already now have talked about a number 00:43:31.790 --> 00:43:35.300 align:middle line:84% of distinct different interactions that 00:43:35.300 --> 00:43:37.940 align:middle line:84% are responsible for creating the three-dimensional 00:43:37.940 --> 00:43:40.190 align:middle line:90% stereochemistry of the protein. 00:43:40.190 --> 00:43:43.760 align:middle line:84% First of all, there are the disulfide bonds, 00:43:43.760 --> 00:43:47.210 align:middle line:84% which create chain-to-chain covalent interactions. 00:43:47.210 --> 00:43:49.850 align:middle line:84% There are the hydrogen bonds in which different side 00:43:49.850 --> 00:43:53.060 align:middle line:84% chains can-- different chains can interact with one another. 00:43:53.060 --> 00:43:56.280 align:middle line:84% And there are these hydrophobic and hydrophilic interactions. 00:43:56.280 --> 00:43:59.210 align:middle line:84% And there are some relatively inconsequential van der Waals 00:43:59.210 --> 00:44:01.405 align:middle line:84% interactions, which are really not worth discussing, 00:44:01.405 --> 00:44:03.530 align:middle line:84% although some people get really excited about them. 00:44:03.530 --> 00:44:05.720 align:middle line:90% But we won't. 00:44:05.720 --> 00:44:10.190 align:middle line:84% So here, we now begin to see that we have really interesting 00:44:10.190 --> 00:44:13.100 align:middle line:84% polypeptides, unlike the boring polypeptides that 00:44:13.100 --> 00:44:20.320 align:middle line:84% are ultimately the way one must judge carbohydrates. 00:44:20.320 --> 00:44:22.330 align:middle line:84% Some people think carbohydrate chemistry 00:44:22.330 --> 00:44:23.500 align:middle line:90% is really interesting. 00:44:23.500 --> 00:44:26.170 align:middle line:84% But entre nous, it really isn't that interesting 00:44:26.170 --> 00:44:28.750 align:middle line:84% because you just have the same monomer 00:44:28.750 --> 00:44:31.240 align:middle line:90% in 100 or 500 stretches. 00:44:31.240 --> 00:44:33.250 align:middle line:84% Here, a protein is much more interesting 00:44:33.250 --> 00:44:35.800 align:middle line:84% because of this enormous variability 00:44:35.800 --> 00:44:39.610 align:middle line:84% in amino acid sequence and the consequent ability 00:44:39.610 --> 00:44:45.520 align:middle line:84% to create all kinds of chemical reactivities and structures 00:44:45.520 --> 00:44:48.730 align:middle line:84% because of these 20 different amino acids. 00:44:48.730 --> 00:44:51.190 align:middle line:84% If we were to imagine life on another planet 00:44:51.190 --> 00:44:53.310 align:middle line:84% and we imagine that there were, let's say, 00:44:53.310 --> 00:44:57.190 align:middle line:84% amino acid-like molecules that were part of life, 00:44:57.190 --> 00:45:00.160 align:middle line:84% maybe that other life wouldn't have exactly the same 20 00:45:00.160 --> 00:45:02.230 align:middle line:90% amino acids as we do. 00:45:02.230 --> 00:45:06.250 align:middle line:84% It almost certainly would be a water-based, the way we are. 00:45:06.250 --> 00:45:09.790 align:middle line:84% But it would also rely on hydrogen bonds, 00:45:09.790 --> 00:45:14.770 align:middle line:84% and hydrophilicity, and hydrophobicity interactions 00:45:14.770 --> 00:45:17.620 align:middle line:84% in order to dictate the three-dimensional structure. 00:45:17.620 --> 00:45:20.000 align:middle line:84% In the absence of this very specific 00:45:20.000 --> 00:45:22.460 align:middle line:84% three-dimensional structure, I will tell you 00:45:22.460 --> 00:45:24.930 align:middle line:84% that this enzyme could not function. 00:45:24.930 --> 00:45:26.580 align:middle line:84% And if you were to take this enzyme, 00:45:26.580 --> 00:45:28.080 align:middle line:84% if it were a typical enzyme, and you 00:45:28.080 --> 00:45:31.100 align:middle line:84% were to heat it up briefly, even often 00:45:31.100 --> 00:45:35.300 align:middle line:84% slightly above normal body temperature, it might denature, 00:45:35.300 --> 00:45:39.950 align:middle line:84% i.e. it might lose its three dimensional structure 00:45:39.950 --> 00:45:40.880 align:middle line:90% irreversibly. 00:45:40.880 --> 00:45:45.080 align:middle line:84% And once it were denatured-- once it was denatured, 00:45:45.080 --> 00:45:47.120 align:middle line:84% this process of denaturation, it might not 00:45:47.120 --> 00:45:50.660 align:middle line:84% be able to spontaneously assume that pre-existing three 00:45:50.660 --> 00:45:53.090 align:middle line:84% dimensional configuration and therefore would forever 00:45:53.090 --> 00:45:54.540 align:middle line:90% be inactive. 00:45:54.540 --> 00:45:56.600 align:middle line:84% That means to say, very explicitly, 00:45:56.600 --> 00:45:58.700 align:middle line:84% that even though the amino acids that 00:45:58.700 --> 00:46:01.160 align:middle line:84% are creating that active catalytic site 00:46:01.160 --> 00:46:04.340 align:middle line:84% remain there, their highly specific 00:46:04.340 --> 00:46:08.750 align:middle line:84% three-dimensional disposition is critical for the continued 00:46:08.750 --> 00:46:10.280 align:middle line:90% actions of this enzyme. 00:46:10.280 --> 00:46:15.020 align:middle line:84% And once their three-dimensional dispositions are shifted around 00:46:15.020 --> 00:46:16.790 align:middle line:84% through the process of interactions, 00:46:16.790 --> 00:46:20.510 align:middle line:84% then we have trouble because the enzyme can no longer 00:46:20.510 --> 00:46:22.670 align:middle line:90% do its assigned task. 00:46:22.670 --> 00:46:27.530 align:middle line:84% We're going to go now to an even higher order of complexity, 00:46:27.530 --> 00:46:28.670 align:middle line:90% in one sense. 00:46:28.670 --> 00:46:32.480 align:middle line:84% We're going to go to the royalty of the macromolecules, which 00:46:32.480 --> 00:46:34.100 align:middle line:90% are the nucleic acids. 00:46:34.100 --> 00:46:36.500 align:middle line:84% Of course, protein chemists would take great umbrage 00:46:36.500 --> 00:46:39.530 align:middle line:84% at the very notion that there are 00:46:39.530 --> 00:46:41.330 align:middle line:90% things better than proteins. 00:46:41.330 --> 00:46:44.498 align:middle line:84% But the fact of the matter is, entre nous, there are-- 00:46:44.498 --> 00:46:46.290 align:middle line:84% I can't show you that overhead because it's 00:46:46.290 --> 00:46:49.280 align:middle line:84% from the other textbook, which is copyright. 00:46:49.280 --> 00:46:50.568 align:middle line:90% And we're being filmed. 00:46:50.568 --> 00:46:52.610 align:middle line:84% How many people have had the backs of their heads 00:46:52.610 --> 00:46:55.930 align:middle line:90% immortalized on these videos? 00:46:55.930 --> 00:46:59.350 align:middle line:84% Did you call home and ask anybody to identify you? 00:46:59.350 --> 00:47:00.440 align:middle line:90% AUDIENCE: [INAUDIBLE] 00:47:00.440 --> 00:47:01.690 align:middle line:90% ROBERT WEINBERG: I don't know. 00:47:01.690 --> 00:47:03.340 align:middle line:90% But soon, you'll be-- 00:47:03.340 --> 00:47:06.680 align:middle line:84% each of us has the limelight for 15 minutes in a lifetime, 00:47:06.680 --> 00:47:07.180 align:middle line:90% right? 00:47:07.180 --> 00:47:08.780 align:middle line:90% So you'll have your 15 minutes. 00:47:08.780 --> 00:47:09.280 align:middle line:90% OK. 00:47:09.280 --> 00:47:11.530 align:middle line:90% Here are some nucleic acids. 00:47:11.530 --> 00:47:15.190 align:middle line:84% And let's look at these nucleic acids and the way 00:47:15.190 --> 00:47:16.520 align:middle line:90% they're put together. 00:47:16.520 --> 00:47:19.150 align:middle line:84% Keep in mind, to anticipate what we're going to say next time, 00:47:19.150 --> 00:47:21.610 align:middle line:84% once again, we want to make end to end aggregates. 00:47:21.610 --> 00:47:25.000 align:middle line:90% We want to polymerize molecules. 00:47:25.000 --> 00:47:29.170 align:middle line:84% And in this case, we want to do so, once again, 00:47:29.170 --> 00:47:31.630 align:middle line:90% through a dehydration reaction. 00:47:31.630 --> 00:47:33.550 align:middle line:84% And moreover, just to look at the building 00:47:33.550 --> 00:47:36.400 align:middle line:84% blocks of nucleic acids, we start again, in this case, 00:47:36.400 --> 00:47:37.420 align:middle line:90% with two pentoses. 00:47:37.420 --> 00:47:38.920 align:middle line:84% Recall that they have four carbons-- 00:47:38.920 --> 00:47:40.720 align:middle line:90% 1, 2, 3, 4. 00:47:40.720 --> 00:47:42.265 align:middle line:90% No, did I say four? 00:47:42.265 --> 00:47:45.310 align:middle line:90% You know I meant five-- 00:47:45.310 --> 00:47:47.110 align:middle line:90% 1, 2, 3, 4, 5. 00:47:47.110 --> 00:47:49.614 align:middle line:84% So whenever I say four from now, on I mean-- 00:47:49.614 --> 00:47:51.350 align:middle line:90% AUDIENCE: Five. 00:47:51.350 --> 00:47:54.740 align:middle line:84% ROBERT WEINBERG: Or whenever I say four, I may also mean four. 00:47:54.740 --> 00:47:55.250 align:middle line:90% OK. 00:47:55.250 --> 00:47:57.440 align:middle line:90% 1, 2, 3, 4, 5. 00:47:57.440 --> 00:48:01.580 align:middle line:84% And let's look at the two basic kinds of pentose molecules 00:48:01.580 --> 00:48:04.970 align:middle line:84% that are present in nucleic acid because they 00:48:04.970 --> 00:48:09.480 align:middle line:84% define the essential difference between DNA and RNA. 00:48:09.480 --> 00:48:12.360 align:middle line:84% Here's a regular old rather familiar kind 00:48:12.360 --> 00:48:14.880 align:middle line:90% of pentose with five carbons. 00:48:14.880 --> 00:48:17.310 align:middle line:84% And here's an unfamiliar kind of pentose, 00:48:17.310 --> 00:48:19.440 align:middle line:90% which we call deoxyribose. 00:48:19.440 --> 00:48:20.310 align:middle line:90% Why? 00:48:20.310 --> 00:48:21.970 align:middle line:84% Because if you look really carefully, 00:48:21.970 --> 00:48:23.887 align:middle line:84% you'll see that the hydroxyl group here, which 00:48:23.887 --> 00:48:26.280 align:middle line:84% should be present in any self-respecting pentose, 00:48:26.280 --> 00:48:28.470 align:middle line:84% is missing and is replaced simply 00:48:28.470 --> 00:48:32.370 align:middle line:84% by a hydrogen group, i.e. it's lost its oxygen, 00:48:32.370 --> 00:48:35.310 align:middle line:84% whence cometh the word deoxyribose, 00:48:35.310 --> 00:48:39.720 align:middle line:84% and ultimately clearly the word deoxyribose nucleic acid. 00:48:39.720 --> 00:48:42.750 align:middle line:84% And one of the attributes, one of the virtues 00:48:42.750 --> 00:48:45.030 align:middle line:84% of carbohydrates, as we discussed last time, 00:48:45.030 --> 00:48:47.920 align:middle line:84% were these numerous hydroxyl groups, 00:48:47.920 --> 00:48:52.110 align:middle line:84% which represent opportunities for all kinds of dehydration 00:48:52.110 --> 00:48:55.440 align:middle line:84% reactions, which can enable one to build much more 00:48:55.440 --> 00:48:56.860 align:middle line:90% complex molecules. 00:48:56.860 --> 00:49:00.280 align:middle line:84% And here, we see the structure of, for example, 00:49:00.280 --> 00:49:04.380 align:middle line:84% a deoxyribonucleotide whose detailed structure 00:49:04.380 --> 00:49:06.570 align:middle line:90% we'll get into next time. 00:49:06.570 --> 00:49:09.780 align:middle line:84% But just let's look at how these hydroxyl groups have been used. 00:49:09.780 --> 00:49:12.330 align:middle line:84% The hydroxyl group, in this case in DNA-- 00:49:12.330 --> 00:49:18.240 align:middle line:84% and by the way, notice that the structure I've shown here-- 00:49:18.240 --> 00:49:19.970 align:middle line:84% there's a side chain attached here 00:49:19.970 --> 00:49:21.590 align:middle line:90% and a side chain attached here. 00:49:21.590 --> 00:49:23.930 align:middle line:84% And neither of those depends on whether or not 00:49:23.930 --> 00:49:27.140 align:middle line:84% there's a hydrogen or a hydroxyl right here. 00:49:27.140 --> 00:49:28.970 align:middle line:90% And look what's happened here. 00:49:28.970 --> 00:49:32.420 align:middle line:84% Here, we have this hydroxyl, over here, 00:49:32.420 --> 00:49:35.120 align:middle line:84% to which a base has been attached covalently, 00:49:35.120 --> 00:49:37.920 align:middle line:84% once again by a dehydration reaction. 00:49:37.920 --> 00:49:41.660 align:middle line:84% And here, we have a situation where actually three phosphate 00:49:41.660 --> 00:49:44.120 align:middle line:84% groups have been attached to the hydroxyl group 00:49:44.120 --> 00:49:46.100 align:middle line:90% in this direction. 00:49:46.100 --> 00:49:48.530 align:middle line:84% And this represents the basic building blocks 00:49:48.530 --> 00:49:50.010 align:middle line:90% of nucleic acids. 00:49:50.010 --> 00:49:52.550 align:middle line:84% Now, one of the things that's going to be really important 00:49:52.550 --> 00:49:53.810 align:middle line:84% and that you're going to have to memorize-- 00:49:53.810 --> 00:49:56.190 align:middle line:84% I told you weren't going to have to memorize anything. 00:49:56.190 --> 00:49:57.768 align:middle line:84% But you didn't believe me, did you? 00:49:57.768 --> 00:49:58.310 align:middle line:90% AUDIENCE: No. 00:49:58.310 --> 00:49:59.000 align:middle line:90% ROBERT WEINBERG: Good. 00:49:59.000 --> 00:49:59.600 align:middle line:90% OK. 00:49:59.600 --> 00:50:01.683 align:middle line:84% One of the things you're going to have to memorize 00:50:01.683 --> 00:50:03.260 align:middle line:90% is the numbering system here. 00:50:03.260 --> 00:50:07.220 align:middle line:90% This is number 1, 2, 3, 4, 5. 00:50:07.220 --> 00:50:10.860 align:middle line:84% Or to be totally frank-- and you know I'm always that-- 00:50:10.860 --> 00:50:15.200 align:middle line:84% 1-prime, 2-prime, 3-prime, 4-prime, 5-prime. 00:50:15.200 --> 00:50:17.000 align:middle line:84% And that numbering system, it turns out, 00:50:17.000 --> 00:50:20.910 align:middle line:84% is going to be very important for our subsequent discussions. 00:50:20.910 --> 00:50:24.270 align:middle line:84% Notice here that, for example, it's here 00:50:24.270 --> 00:50:27.300 align:middle line:84% at the 2-prime position that this deoxyribose is 00:50:27.300 --> 00:50:34.750 align:middle line:84% lacking the oxygen that is present normally in RNA. 00:50:34.750 --> 00:50:38.760 align:middle line:84% And with all this in mind, we will wait in great suspense 00:50:38.760 --> 00:50:41.400 align:middle line:84% until Wednesday when we actually talk 00:50:41.400 --> 00:50:45.630 align:middle line:84% about how this is exploited to make highly complex polymers. 00:50:45.630 --> 00:50:46.890 align:middle line:90% Have a good two days. 00:50:46.890 --> 00:50:49.370 align:middle line:90% See you Wednesday at 10:00. 00:50:49.370 --> 00:51:38.000 align:middle line:90%