1 00:00:00 --> 00:00:04 I've emphasized in the first lecture, you know, that there's a lot of 2 00:00:04 --> 00:00:08 stuff that happens just in your ordinary life. 3 00:00:08 --> 00:00:12 I saw two examples of this. Yesterday's Boston Globe, just on 4 00:00:12 --> 00:00:16 the front page there was a discovery about “Heart Cell Discovery Raises 5 00:00:16 --> 00:00:20 Treatment Hopes”. Scientists announced yesterday the 6 00:00:20 --> 00:00:24 discovery of cells in the heart that can create new muscle cells raising 7 00:00:24 --> 00:00:29 hopes that doctors may find dramatic new ways to treat heart disease. 8 00:00:29 --> 00:00:32 The team showed that the cells, which are similar to stem cells, 9 00:00:32 --> 00:00:35 can be expanded from just a few hundred in the laboratory dish up to 10 00:00:35 --> 00:00:38 more than a million. And these can be guiding into 11 00:00:38 --> 00:00:41 becoming the pulsing muscles that power the heart. 12 00:00:41 --> 00:00:44 So when we were talking about those yeast dividing and saying how one 13 00:00:44 --> 00:00:47 cell becomes two, this is a general principle 14 00:00:47 --> 00:00:51 throughout life that cells come from other cells and they divide. 15 00:00:51 --> 00:00:54 And we'll see the relationship to that with DNA replication as we go 16 00:00:54 --> 00:00:57 along. In the case of yeast, as I said, they're just always the 17 00:00:57 --> 00:01:00 same. Your progeny are always the same. 18 00:01:00 --> 00:01:04 But in something like our own cells we start out as a single fertilized 19 00:01:04 --> 00:01:08 cell but somewhere along the way the cells have to become specialized. 20 00:01:08 --> 00:01:12 So the very early ones are the embryonic stem cells. 21 00:01:12 --> 00:01:15 They have the potential to become any cell in the body. 22 00:01:15 --> 00:01:19 But at some point, at one of these cell divisions the cells are going 23 00:01:19 --> 00:01:23 to have to start to become more specialized. And, 24 00:01:23 --> 00:01:27 for example, this one might be a lineage that would lead to heart 25 00:01:27 --> 00:01:31 muscle or to becoming a nerve or something. 26 00:01:31 --> 00:01:35 And at that point it loses its ability to become any cell in the 27 00:01:35 --> 00:01:39 body. And in many cases by the time you get out ultimately to the final 28 00:01:39 --> 00:01:43 cell that's making up the muscle or the nerve or something it has no 29 00:01:43 --> 00:01:47 capacity to regenerate. So that's why, for example, 30 00:01:47 --> 00:01:51 spinal cord injuries are so damaging because nerves at this point cannot 31 00:01:51 --> 00:01:55 be regenerated. Or heart disease, 32 00:01:55 --> 00:02:00 you get a damaged heart we're stuck. This is why this result is exciting. 33 00:02:00 --> 00:02:04 Because there seem to be at least a few cells in the heart that have the 34 00:02:04 --> 00:02:08 capacity to regenerate more heart muscle. Now, this is early on. 35 00:02:08 --> 00:02:13 It hasn't been rigorously shown to be a stem cell. 36 00:02:13 --> 00:02:17 But there's an example from the front of yesterday's paper about 37 00:02:17 --> 00:02:21 something we were virtually alluding to in class. There was also an 38 00:02:21 --> 00:02:26 article about AIDS testing. Again, you know, we're talk more 39 00:02:26 --> 00:02:30 about the HIV-1 virus. And then today on the front page of 40 00:02:30 --> 00:02:35 the Boston Globe yet again is “Romney Draws Fire on Stem Cells”. 41 00:02:35 --> 00:02:39 And you can look at this. But, you know, he's sort of trying 42 00:02:39 --> 00:02:44 to straddle, I guess, between being supportive of research 43 00:02:44 --> 00:02:49 on the one hand and the concerns of the conservatives and the religious 44 00:02:49 --> 00:02:54 right on the other hand, and he's drawing fire from both 45 00:02:54 --> 00:02:59 sides. But it's an issue that is in our society today. 46 00:02:59 --> 00:03:03 You're going to be expected to make decisions on it, 47 00:03:03 --> 00:03:08 to know about it and understand. I'm just trying to drive home that 48 00:03:08 --> 00:03:12 what we're talking about isn't taking place in a vacuum. 49 00:03:12 --> 00:03:17 Nobody emailed me an idea as to what happened here. 50 00:03:17 --> 00:03:22 I showed you this little movie. This is water that is cooled below 51 00:03:22 --> 00:03:26 the freezing point but hasn't formed ice crystals, but if we put a little 52 00:03:26 --> 00:03:31 bit of this pseudomonas syringae in it then somehow that super-cooled 53 00:03:31 --> 00:03:35 water turned into ice. And I told you it was a protein on 54 00:03:35 --> 00:03:39 the surface. Nobody had any ideas. So why don't you turn to whoever is 55 00:03:39 --> 00:03:43 close to you and you can talk about it for 30 seconds and see if anybody 56 00:03:43 --> 00:03:46 can come up with an idea as to why. All right? I won't look. You know, 57 00:03:46 --> 00:03:50 just go ahead. Talk to somebody and come up with 58 00:03:50 --> 00:04:32 an idea. 59 00:04:32 --> 00:04:36 OK. Well, let's see. Did we manage to get any ideas? 60 00:04:36 --> 00:04:41 Anybody got the courage to try and guess what that protein might be 61 00:04:41 --> 00:04:45 doing? Pardon? It's a nonpolar molecule. 62 00:04:45 --> 00:04:50 It's not disturbing the bonds. It's an interesting idea. Do you 63 00:04:50 --> 00:04:55 have an idea then, are you able to extend that as to 64 00:04:55 --> 00:05:00 why then the ice would start to form? 65 00:05:00 --> 00:05:04 I mean it's certainly true that nonpolar bonds sort of interfere 66 00:05:04 --> 00:05:08 with the water. That's something we've talked about. 67 00:05:08 --> 00:05:12 Let's see. Any other ideas? Yeah? That's a version of the same 68 00:05:12 --> 00:05:16 idea, I think, hydrophobic because you think it 69 00:05:16 --> 00:05:20 wants to repel the water and push it together. That's interesting. 70 00:05:20 --> 00:05:24 You're sort of getting closer on these. Yeah? 71 00:05:24 --> 00:05:40 There it is. If you were to design 72 00:05:40 --> 00:05:45 a protein that basically could bind water molecules in a lattice that 73 00:05:45 --> 00:05:49 mimicked what you found in ice then the water molecules coming up and 74 00:05:49 --> 00:05:54 binding to these little pockets in the protein would present then a 75 00:05:54 --> 00:05:59 little field of stable water molecules that looked to the next 76 00:05:59 --> 00:06:04 water molecule like it was part of an ice crystal. 77 00:06:04 --> 00:06:08 And that's indeed how that bacterium does that trick. 78 00:06:08 --> 00:06:13 It's called the ice nucleation protein. And they do things like 79 00:06:13 --> 00:06:17 take this bacterium and they put it into things like when you're doing 80 00:06:17 --> 00:06:22 snowmaking, you put this in and then you spray the super-cooled water, 81 00:06:22 --> 00:06:26 and this makes it go into ice crystals and then it helps you get 82 00:06:26 --> 00:06:31 nice snow for ski resorts and things. 83 00:06:31 --> 00:06:37 That's at least one of the areas where it's used. 84 00:06:37 --> 00:06:43 OK. So I'm just going to show you this movie again. 85 00:06:43 --> 00:06:49 These are just baker's yeast, saccharomyces cerevisiae, a kind of 86 00:06:49 --> 00:06:55 single-celled yeast that's used in baking bread or making beer. 87 00:06:55 --> 00:07:00 And here we're seeing cells divide. And this particular kind of yeast 88 00:07:00 --> 00:07:04 has a way of doing, it kind of buds the daughter off 89 00:07:04 --> 00:07:07 from the side. Some double and then split down the 90 00:07:07 --> 00:07:11 middle. But you can see what's going on. There's a lot of cell 91 00:07:11 --> 00:07:14 growth going on. And the issue that we're going to 92 00:07:14 --> 00:07:18 address now is where does the energy come that's needed to do that? 93 00:07:18 --> 00:07:22 You know from your own experience that to build things, 94 00:07:22 --> 00:07:25 to make things takes energy. You cannot put up a bridge, you 95 00:07:25 --> 00:07:29 cannot put up a building, you cannot build a computer chip 96 00:07:29 --> 00:07:32 without somehow putting energy in. You're taking a bunch of matter in 97 00:07:32 --> 00:07:36 the universe and ordering it in a very specific way making new 98 00:07:36 --> 00:07:40 contacts that didn't be there. It's an energy-requiring process. 99 00:07:40 --> 00:07:43 And I'm going to talk today about where that energy comes from. 100 00:07:43 --> 00:07:47 And then I want to tell you a little bit, just a very brief 101 00:07:47 --> 00:07:50 historical thing along the way, because a point I've emphasized here 102 00:07:50 --> 00:07:54 is biology is an experimental science. And many of the greatest 103 00:07:54 --> 00:07:58 discoveries weren't because somebody had the idea and then went 104 00:07:58 --> 00:08:02 out to prove it. Very often we didn't even understand 105 00:08:02 --> 00:08:07 how it worked. And somebody was investigating a 106 00:08:07 --> 00:08:11 phenomenon, found some peculiar things, and then began to get 107 00:08:11 --> 00:08:16 insights. And the insights were what then led to a fundamental 108 00:08:16 --> 00:08:21 increase in our understanding. And this little bit of history 109 00:08:21 --> 00:08:26 involves some names that you see on the MIT buildings around here. 110 00:08:26 --> 00:08:31 One is Lavoisier who is a French scientist. 111 00:08:31 --> 00:08:39 And he was studying what happened when grapes were converted into wine, 112 00:08:39 --> 00:08:47 a good topic for a French scientist to be studying. 113 00:08:47 --> 00:08:55 So, in essence, what he was studying was glucose 114 00:08:55 --> 00:09:03 being converted to two molecules, excuse me, of -- 115 00:09:03 --> 00:09:12 -- ethanol and two molecules of 116 00:09:12 --> 00:09:20 carbon dioxide. This transformation, 117 00:09:20 --> 00:09:28 there's C6H12O6. Remember, carbohydrates have that composition. 118 00:09:28 --> 00:09:34 And so he was studying that. 119 00:09:34 --> 00:09:39 He managed to figure out that's what happened to the sugar when you 120 00:09:39 --> 00:09:44 were making the wine. And at that point he got beheaded. 121 00:09:44 --> 00:09:49 That terminated that part of his investigation. 122 00:09:49 --> 00:09:54 But this problem was then picked up by Lois Pasteur who, 123 00:09:54 --> 00:09:59 again, his name is on one of the MIT buildings. 124 00:09:59 --> 00:10:02 He worked in France as well. There's a Pasteur Institute in 125 00:10:02 --> 00:10:06 Paris. There's a nice museum in Lille in Northern France that has a 126 00:10:06 --> 00:10:10 lot of this. But he grew up in Arbois which is a town in sort of 127 00:10:10 --> 00:10:14 Eastern France that, as you can see from the little 128 00:10:14 --> 00:10:18 picture of the village, winemaking was a major industry. 129 00:10:18 --> 00:10:22 So he was interested in that probably from when he was a small, 130 00:10:22 --> 00:10:26 small kid, although probably not dressed like that. But anyway. 131 00:10:26 --> 00:10:31 So one of the issues that he took on, which was a real problem for the 132 00:10:31 --> 00:10:37 wine growers in his little town and in France in general was sometimes 133 00:10:37 --> 00:10:42 wines would go bad. They'd come out sour and couldn't 134 00:10:42 --> 00:10:48 be drunk and then you'd lose all the profit that would have come from 135 00:10:48 --> 00:10:53 that wine. So there was a lot of interest in trying to figure out how 136 00:10:53 --> 00:10:59 to prevent wines from going bad. And so Lois Pasteur started to 137 00:10:59 --> 00:11:04 study this. And he discovered that there was this conversion that had 138 00:11:04 --> 00:11:10 been figured out now of two ethanol and two carbon dioxide. 139 00:11:10 --> 00:11:15 So this was a conversion. And we now refer to it generally as 140 00:11:15 --> 00:11:21 “a fermentation”. But what he discovered with this 141 00:11:21 --> 00:11:33 conversion occurred -- 142 00:11:33 --> 00:11:39 -- if yeast were present. That the rate of this conversion 143 00:11:39 --> 00:11:45 varied as the number of yeast, so it went faster if there were more 144 00:11:45 --> 00:11:52 yeast. And the yeast stopped growing -- 145 00:11:52 --> 00:12:04 -- when the sugar ran out. 146 00:12:04 --> 00:12:08 So what he discovered here was a correlation. He hadn't proven 147 00:12:08 --> 00:12:12 anything. He just saw that if you watch sugar go to ethanol there were 148 00:12:12 --> 00:12:16 yeast around, if you had more yeast it went faster, 149 00:12:16 --> 00:12:21 and when you ran out of sugar the yeast stopped growing. 150 00:12:21 --> 00:12:25 There was something connected here. So he came up with the idea that 151 00:12:25 --> 00:12:29 the yeast were responsible for this conversion that was happening 152 00:12:29 --> 00:12:33 when you made wine. And it was further helped out in 153 00:12:33 --> 00:12:37 this because he discovered an alternative -- 154 00:12:37 --> 00:12:48 -- conversion in which C6H12O6 went 155 00:12:48 --> 00:12:56 instead to give two molecules of CH3CHOH. This molecule which you 156 00:12:56 --> 00:13:05 know, galactic acid, it too has C6H12O6 on both sides of 157 00:13:05 --> 00:13:14 the equation but it's a different molecule. 158 00:13:14 --> 00:13:18 And what he found was that this is the lactic acid you know as what's 159 00:13:18 --> 00:13:22 in yogurt. It makes yogurt sour. Or if you exercise really hard and 160 00:13:22 --> 00:13:26 your muscles are sore that's because you accumulate lactic acid in your 161 00:13:26 --> 00:13:31 muscles, and I'll tell you why that is in the next lecture. 162 00:13:31 --> 00:13:35 But what the other thing that Pasteur realized was when you got 163 00:13:35 --> 00:13:39 this alternative conversion you didn't have yeast present, 164 00:13:39 --> 00:13:43 you had some other organism. And so that was a huge advance just 165 00:13:43 --> 00:13:47 of practical value to the winemakers because they knew they had to have 166 00:13:47 --> 00:13:51 yeast in there to get wine and there problems were coming when some other 167 00:13:51 --> 00:13:55 organism that wasn't yeast got in there and it did something different 168 00:13:55 --> 00:13:59 with the sugar and made it into lactic acid instead of making it 169 00:13:59 --> 00:14:04 into ethanol and carbon dioxide. So there was Pasteur working away on 170 00:14:04 --> 00:14:10 a practical problem and it was, you know, a really major advance to 171 00:14:10 --> 00:14:16 the winemaking industry for him to do this, but it also then sort of 172 00:14:16 --> 00:14:22 unexpectedly led to another issue. And that was why were the yeast 173 00:14:22 --> 00:14:28 doing this? Because one of the things that Lavoisier had noticed 174 00:14:28 --> 00:14:34 and Pasteur noticed was that you did this conversion. 175 00:14:34 --> 00:14:40 The two ethanol plus two carbon 176 00:14:40 --> 00:14:45 dioxide. But you could account for virtually all of the carbon and 177 00:14:45 --> 00:14:51 hydrogens and oxygens that started out as sugar and seemed like 178 00:14:51 --> 00:14:56 virtually of them showed up in the ethanol and the carbon dioxide. 179 00:14:56 --> 00:15:01 So why was the yeast doing this? And the idea began to develop out of 180 00:15:01 --> 00:15:05 that was that rather than being used to make biomass, 181 00:15:05 --> 00:15:10 in which case you would have expected to see a whole lot of mass 182 00:15:10 --> 00:15:14 in the yeast cells and no so much up here, that instead most of this 183 00:15:14 --> 00:15:19 sugar was being used to make energy and that somehow the cell was 184 00:15:19 --> 00:15:23 getting the energy necessary to all that synthetic work involved in cell 185 00:15:23 --> 00:15:28 division by carrying out this conversion. 186 00:15:28 --> 00:15:34 And there's a fundamental relationship then between chemical 187 00:15:34 --> 00:15:40 energy and whether a reaction can proceed. And I'll just take it 188 00:15:40 --> 00:15:47 through in sort of your typical introductory chemistry reaction, 189 00:15:47 --> 00:15:53 A plus B going to C plus D. You know, there are certain classes of 190 00:15:53 --> 00:16:00 reactions that will go almost to completion. 191 00:16:00 --> 00:16:04 Probably an overstatement to say it's to go to completion, 192 00:16:04 --> 00:16:08 but it's effectively over here. Those are termed irreversible 193 00:16:08 --> 00:16:12 reactions, and there are certainly some of them. If I have hydrogen 194 00:16:12 --> 00:16:17 and oxygen and I light a little match, you pretty much go all the 195 00:16:17 --> 00:16:21 way to making water with a great big boom and no hydrogen or not much 196 00:16:21 --> 00:16:25 hydrogen and oxygen left on the other side. However, 197 00:16:25 --> 00:16:30 most reactions that one finds in nature don't have that quality. 198 00:16:30 --> 00:16:36 Instead they are going forward at some rate and back at another. 199 00:16:36 --> 00:16:42 And they reach eventually an equilibrium that's characterized by 200 00:16:42 --> 00:16:48 what's known as an equilibrium constant which is the product of the 201 00:16:48 --> 00:16:54 concentrations of the products over the product of the concentration of 202 00:16:54 --> 00:16:59 the reactants. And that's a characteristic of every 203 00:16:59 --> 00:17:03 particular chemical reaction. And we really have to worry about 204 00:17:03 --> 00:17:07 this in biology because if everything was irreversible that 205 00:17:07 --> 00:17:11 would be fine, but in order to do all this 206 00:17:11 --> 00:17:16 synthetic work you have to deal with a lot of reactions that aren't going 207 00:17:16 --> 00:17:20 to go to completion. And nature has had to figure out a 208 00:17:20 --> 00:17:24 way of doing that, just the same way that bridges and 209 00:17:24 --> 00:17:28 buildings don't spontaneously assemble and engineers and others 210 00:17:28 --> 00:17:33 have had to work out ways of putting all of those things together. 211 00:17:33 --> 00:17:39 So at some level you see the same kind of problem. 212 00:17:39 --> 00:17:45 Now, there's a way of expressing this energy associated with a 213 00:17:45 --> 00:17:51 chemical reaction that can be used to directly calculate whether a 214 00:17:51 --> 00:17:57 reaction is going to go and how far it will go. And a person who did 215 00:17:57 --> 00:18:03 this work is another person who's on one of the MIT buildings. 216 00:18:03 --> 00:18:09 It was [Willard? Gibbs who was a faculty member 217 00:18:09 --> 00:18:15 chemist who worked at Yale in the 1980s, excuse me, 218 00:18:15 --> 00:18:21 1800s, and he came up with an expression that's now known as 219 00:18:21 --> 00:18:27 “Gibbs free energy”. And what's important about this way 220 00:18:27 --> 00:18:33 of talking about the energy change associated with the chemical 221 00:18:33 --> 00:18:39 reaction is it considers not only the internal energy of the system 222 00:18:39 --> 00:18:44 but also the change in disorder. Or another way of saying that, 223 00:18:44 --> 00:18:48 for those of you who've run into the laws of thermodynamics, 224 00:18:48 --> 00:18:52 it combines the first and second laws of thermodynamics. 225 00:18:52 --> 00:18:56 And you have to consider both of those if you're going to consider 226 00:18:56 --> 00:19:01 whether a reaction will go. And you cannot measure an absolute 227 00:19:01 --> 00:19:07 free energy but you can measure a change. And this is the equation. 228 00:19:07 --> 00:19:13 It's the change associated with a chemical reaction is equal to the 229 00:19:13 --> 00:19:19 change associated with the chemical reaction under some set of standard 230 00:19:19 --> 00:19:25 conditions times RT times the log of the concentration of the products 231 00:19:25 --> 00:19:32 multiplied together over the concentration of the reactants. 232 00:19:32 --> 00:19:38 So if we could just go to the same example we were just thinking about, 233 00:19:38 --> 00:19:45 the energy change with that reaction that we were considering 234 00:19:45 --> 00:19:54 would have been this. 235 00:19:54 --> 00:20:07 So this is the energy change -- 236 00:20:07 --> 00:20:10 -- associated with the concentrations -- 237 00:20:10 --> 00:20:19 -- the reactants and products that 238 00:20:19 --> 00:20:27 we're considering. 239 00:20:27 --> 00:20:32 This is the energy change under standard, or the term standard 240 00:20:32 --> 00:20:38 conditions where everything, each reactant, each product is 241 00:20:38 --> 00:20:44 present under one molar concentrations. 242 00:20:44 --> 00:20:50 So not something you'd ever find in most cases, but it's a frame of 243 00:20:50 --> 00:20:56 reference. And then this is the universal gas constant -- 244 00:20:56 --> 00:21:04 -- which is two times ten to the 245 00:21:04 --> 00:21:11 minus third kilocalories per mole per degree Calvin, 246 00:21:11 --> 00:21:17 the temperature in absolute. This is the temperature in degrees 247 00:21:17 --> 00:21:24 Calvin. And the temperature for most biology, most life is around 25 248 00:21:24 --> 00:21:31 degrees Centigrade, so that's equal to 298 degrees 249 00:21:31 --> 00:21:38 Calvin, which is about equal to 300 degrees Calvin. So for most -- 250 00:21:38 --> 00:21:43 And since the range in which life can occur on an absolute temperature 251 00:21:43 --> 00:21:48 scale is really pretty small, it sort of fluctuates in only very 252 00:21:48 --> 00:21:53 minor ways around 25 degrees Centigrade, then for most of the 253 00:21:53 --> 00:21:59 biological reactions we'll be thinking about this RT number is 254 00:21:59 --> 00:22:08 about 0.6 kilocalories per mole. 255 00:22:08 --> 00:22:15 Now, biochemists actually have a special form of free energy they use, 256 00:22:15 --> 00:22:23 which we put a delta G prime. And in this case the delta G prime 257 00:22:23 --> 00:22:31 is equal to delta G prime under a set of standard conditions plus RT 258 00:22:31 --> 00:22:39 natural log of C products over the reactants. 259 00:22:39 --> 00:22:46 But the assumption is made that the reaction is in water which, 260 00:22:46 --> 00:22:54 I mentioned the other day, is 55 molar. Yeah? 261 00:22:54 --> 00:23:03 This is the degree Celsius. 262 00:23:03 --> 00:23:08 I've just expressed it in degrees Calvin. 263 00:23:08 --> 00:23:21 Sorry. My mistake. 264 00:23:21 --> 00:23:27 Excuse me. Because I was wrong is why. OK. Thanks for catching 265 00:23:27 --> 00:23:32 that. All right. So water is very concentrated. 266 00:23:32 --> 00:23:36 And so under these conditions the other convention is then you can set 267 00:23:36 --> 00:23:41 the hydrogen ions and water molecules to one. 268 00:23:41 --> 00:23:46 And you don't have to think about them when we're doing this. 269 00:23:46 --> 00:23:50 This is a convention that biochemists do. 270 00:23:50 --> 00:23:55 Now, this free energy, the delta G that gives free energy 271 00:23:55 --> 00:24:06 is a thermodynamic -- 272 00:24:06 --> 00:24:12 -- property. And I'll just share with you the same visual image I've 273 00:24:12 --> 00:24:18 had since I was an undergrad, which I think is not a bad way of 274 00:24:18 --> 00:24:24 thinking about it trying to understand what happens, 275 00:24:24 --> 00:24:30 that if we have a plot of the free energy as a function of what happens 276 00:24:30 --> 00:24:36 as the reaction goes along so that we have A plus B here and 277 00:24:36 --> 00:24:42 C plus D down here. When you go from reaction to 278 00:24:42 --> 00:24:46 products, the way I've drawn it, some kind of energy is given off in 279 00:24:46 --> 00:24:50 this kind of reaction. And if you know that you will know 280 00:24:50 --> 00:24:54 then that the reaction will be able to go forward because it's able to 281 00:24:54 --> 00:24:58 give off energy just the same way hydrogen and oxygen give off a lot 282 00:24:58 --> 00:25:02 of heat and stuff, and you know that reaction really 283 00:25:02 --> 00:25:06 goes a long way to completion. So it's kind of as if you were out 284 00:25:06 --> 00:25:11 here on your spring break on your skis already to go down the black 285 00:25:11 --> 00:25:16 diamond hill, you know, you can sort of see what would 286 00:25:16 --> 00:25:20 happen. Now, because it's a thermodynamic property it doesn't 287 00:25:20 --> 00:25:25 matter what route you take to get from the reactions to the products. 288 00:25:25 --> 00:25:30 So if you go down the double diamond slope or you go down the 289 00:25:30 --> 00:25:35 bunny slope you still end up with the same amount of energy coming out 290 00:25:35 --> 00:25:40 of the reaction. And that's important because if that 291 00:25:40 --> 00:25:46 wasn't true you could make a perpetual motion machine and you'd 292 00:25:46 --> 00:25:51 be very rich. The second thing that's important is that the free 293 00:25:51 --> 00:25:57 energy will tell you what would happen if the reaction went but it 294 00:25:57 --> 00:26:03 will not tell you whether it can go. 295 00:26:03 --> 00:26:07 If I did a demo here and I brought some hydrogen and some oxygen and I 296 00:26:07 --> 00:26:11 mixed them together in a vessel in the front of the class we could all 297 00:26:11 --> 00:26:15 sit here waiting for it to explode. But the likelihood is we would sit 298 00:26:15 --> 00:26:19 here for a very, very long time and not see an 299 00:26:19 --> 00:26:23 explosion, right? And the reason is that in order to 300 00:26:23 --> 00:26:27 get that hydrogen and oxygen close enough together we had to give them 301 00:26:27 --> 00:26:32 some extra energy and push them so they overcome repulsion and stuff. 302 00:26:32 --> 00:26:36 So if you were out here on your skis again getting already to go, 303 00:26:36 --> 00:26:41 but in fact you got off at the wrong stop on the ski lift and you were 304 00:26:41 --> 00:26:46 there, even though there would be energy getting down from here it's 305 00:26:46 --> 00:26:51 not going to happen at any discernable rate given the sort of 306 00:26:51 --> 00:26:56 little bounce in energy you have in your normal lives. 307 00:26:56 --> 00:26:59 So what we're doing when we do hydrogen and oxygen is by putting a 308 00:26:59 --> 00:27:03 match into it or something we're giving it enough energy that 309 00:27:03 --> 00:27:06 actually a few of the molecules get up here, they drop down, 310 00:27:06 --> 00:27:10 then they give up so much energy and heat that all the rest of them get 311 00:27:10 --> 00:27:14 pushed up and the thing goes. But that's sort of not a bad way of 312 00:27:14 --> 00:27:17 thinking about it. And we're going to talk in a minute 313 00:27:17 --> 00:27:21 about what determines how fast reactions go, not whether they go or 314 00:27:21 --> 00:27:25 not. And then, of course, at that point we're going 315 00:27:25 --> 00:27:29 to have to worry about this issue. But before that what I want to show 316 00:27:29 --> 00:27:35 you is that there's a direct relationship between this Gibbs free 317 00:27:35 --> 00:27:41 energy and the equilibrium constant. So we have this, well, what we 318 00:27:41 --> 00:27:46 could do is you have the reaction over there. So let's consider that 319 00:27:46 --> 00:27:52 reaction has come to equilibrium. And that means there'll be no 320 00:27:52 --> 00:27:58 further energy change. So we'll just set the delta G to 321 00:27:58 --> 00:28:04 zero. And that would mean then that delta 322 00:28:04 --> 00:28:10 G prime zero is equal to minus RT concentration C over D over 323 00:28:10 --> 00:28:17 concentration of A over B. You'll recognize this. That's the 324 00:28:17 --> 00:28:23 equilibrium constant, right? I'm sorry. There's a 325 00:28:23 --> 00:28:30 natural log in here. I didn't get it in. OK? 326 00:28:30 --> 00:28:37 So which is equal to minus RT the natural log of the equilibrium 327 00:28:37 --> 00:28:44 constant or the natural log of the equilibrium constant is equal to 328 00:28:44 --> 00:28:51 minus delta G prime zero over RT. Or another way of saying that is 329 00:28:51 --> 00:28:58 the K equilibrium is equal E to the minus delta G prime zero over RT. 330 00:28:58 --> 00:29:02 So if you think back to consequences of an equilibrium constant, 331 00:29:02 --> 00:29:07 if the reaction is going to go almost all the way then there are 332 00:29:07 --> 00:29:12 going to be mostly products, very few reactions, so the K 333 00:29:12 --> 00:29:17 equilibrium will be large. So if a reaction is going to go a 334 00:29:17 --> 00:29:22 long way then the equilibrium constant will be large. 335 00:29:22 --> 00:29:27 And in order for an equilibrium constant to be large then this delta 336 00:29:27 --> 00:29:32 G is going to have to have a large negative sign. So if 337 00:29:32 --> 00:29:44 the reaction -- 338 00:29:44 --> 00:29:52 -- is favorable then K equilibrium will be large and the delta G prime 339 00:29:52 --> 00:30:00 zero will have, at least within the scale of an 340 00:30:00 --> 00:30:08 activation energy, a large negative value. 341 00:30:08 --> 00:30:12 And let me give you a couple of examples. When we talked about 342 00:30:12 --> 00:30:16 carbohydrates, I briefly told you sucrose was what 343 00:30:16 --> 00:30:20 we call a disaccharide, two sugars joined together. 344 00:30:20 --> 00:30:24 What do we do when we join two things together pretty much usually 345 00:30:24 --> 00:30:28 in nature? You split out a molecule of water. 346 00:30:28 --> 00:30:33 So we take a molecule of glucose, a molecule of fructose, both 347 00:30:33 --> 00:30:38 carbohydrates, stick them together and we get table 348 00:30:38 --> 00:30:43 sugar. If we want to reverse that reaction we have to put in a 349 00:30:43 --> 00:30:48 molecule of water and we can run it the other way. 350 00:30:48 --> 00:30:53 We get glucose plus fructose. The K equilibrium for that reaction 351 00:30:53 --> 00:30:59 is 140,000. The delta G prime zero is minus 352 00:30:59 --> 00:31:05 seven kilocalories per mole. So that's an example of what I was 353 00:31:05 --> 00:31:12 just telling you, a fairly large negative value. 354 00:31:12 --> 00:31:19 If we think about a reaction that's not favorable, 355 00:31:19 --> 00:31:26 here's acidic acid. That's what makes vinegar sour. 356 00:31:26 --> 00:31:33 And the hydrogen ion can come off here to give you a hydrogen ion and 357 00:31:33 --> 00:31:41 the negative ion of acidic acid or acetate ion. The equilibrium 358 00:31:41 --> 00:31:48 constant for that one is, what is it, I think two times ten to 359 00:31:48 --> 00:31:56 the minus five. So only a little tiny bit of the 360 00:31:56 --> 00:32:03 acidic acid actually ionizes. And the K equilibrium constant then, 361 00:32:03 --> 00:32:09 excuse me, the delta G prime zero is plus 6.3 kilocalories per mole. 362 00:32:09 --> 00:32:16 So buried in this example is not showing you that a reaction that's 363 00:32:16 --> 00:32:23 unfavorable will have a positive free energy associated with it, 364 00:32:23 --> 00:32:30 whereas one that's favorable will have a negative free energy. 365 00:32:30 --> 00:32:35 This is also sort of telling you why you don't die when you put salad 366 00:32:35 --> 00:32:40 dressing on your salad, because if acidic acid ionized as 367 00:32:40 --> 00:32:45 thoroughly as sulfuric acid and you put an equivalent amount of sulfuric 368 00:32:45 --> 00:32:50 acid on our salads none of us would be here. It's only a little tiny 369 00:32:50 --> 00:32:56 bit that's going, and so that's what's happening. 370 00:32:56 --> 00:33:00 So what this really sets us up for is this fundamental problem in 371 00:33:00 --> 00:33:04 biology, and that is that this reaction here, 372 00:33:04 --> 00:33:09 you can see what it would go, this one doesn't go, but most of the 373 00:33:09 --> 00:33:13 reactions that you have to carry out in biology demand an energy input 374 00:33:13 --> 00:33:17 because they just won't go. We could sort of force this a 375 00:33:17 --> 00:33:22 little bit. We could raise the concentration of the reactions and 376 00:33:22 --> 00:33:26 it would give us a little bit more product, but that's not a useful 377 00:33:26 --> 00:33:32 solution to all the things. So this was a really fundamental 378 00:33:32 --> 00:33:38 problem that had to be solved in evolution in order for life to ever 379 00:33:38 --> 00:33:45 exist. And I'll give you just an example. If we consider taking a 380 00:33:45 --> 00:33:51 couple of molecules of glutamate, which is one of the amino acids we 381 00:33:51 --> 00:33:57 talked about, a couple of molecules of amino and making it into a couple 382 00:33:57 --> 00:34:02 of molecules of glutamine. Now, this is an amino acid needed 383 00:34:02 --> 00:34:05 for making proteins. This is an amino acid needed for 384 00:34:05 --> 00:34:09 making proteins. The cell has to have both of them. 385 00:34:09 --> 00:34:19 Glutamate has two methylene groups 386 00:34:19 --> 00:34:25 and then are carboxyl group that's one of the acid amino acids. 387 00:34:25 --> 00:34:34 And glutamine the side chain -- 388 00:34:34 --> 00:34:39 -- is now amid. The delta G from zero associated 389 00:34:39 --> 00:34:44 with this reaction is plus seven kilocalories per mole, 390 00:34:44 --> 00:34:49 so it's as unfavorable almost as that one we're looking at. 391 00:34:49 --> 00:34:54 In fact, it's worse than the one we're looking at over there. 392 00:34:54 --> 00:34:59 The reason that this is sort of pushing the thing uphill 393 00:34:59 --> 00:35:04 energetically is that the electrons here actually distribute themselves 394 00:35:04 --> 00:35:09 back and forth. So you can kind of think of the 395 00:35:09 --> 00:35:13 molecule as going back and forth between these two forms. 396 00:35:13 --> 00:35:17 And that makes it more stable. And when you stick on the amine 397 00:35:17 --> 00:35:22 group to make the amid it cannot do that, and so you're actually pushing 398 00:35:22 --> 00:35:26 everything energetically uphill. So how does a cell accomplish this? 399 00:35:26 --> 00:35:32 There's energy available. If we consider what happens with 400 00:35:32 --> 00:35:40 C6H12O6 going to two lactate the delta G prime zero associated with 401 00:35:40 --> 00:35:48 that is minus 50 kilocalories per mole. So the cell has got a lot of 402 00:35:48 --> 00:35:56 energy out of making even that simple conversation of a sugar 403 00:35:56 --> 00:36:03 molecule into two lactate. But it somehow has to figure out how 404 00:36:03 --> 00:36:09 to use that energy in order to drive these unfavorable reactions. 405 00:36:09 --> 00:36:16 And the solution, which is really one of the secrets to life, 406 00:36:16 --> 00:36:27 is to use coupled reactions -- 407 00:36:27 --> 00:36:34 -- with a common intermediate. 408 00:36:34 --> 00:36:38 And if you look outside a cell, as Lavoisier did or Pasteur did, 409 00:36:38 --> 00:36:43 this is what you'd see. But if you could look inside the cell and see 410 00:36:43 --> 00:36:48 what's happening when that conversion is being made you'd 411 00:36:48 --> 00:36:53 discover that the full reaction looks like this. 412 00:36:53 --> 00:36:58 It's the sugar molecule plus two molecules of ADP plus two molecules 413 00:36:58 --> 00:37:03 of inorganic phosphate are going to give two molecules of lactate plus 414 00:37:03 --> 00:37:10 two molecules of ATP. What's ATP? It's a ribonucleotide. 415 00:37:10 --> 00:37:29 That's ADP. And what happens when 416 00:37:29 --> 00:37:34 you make ATP is an extra phosphate gets added onto that end 417 00:37:34 --> 00:37:39 of the molecule. So by having yet another phosphate 418 00:37:39 --> 00:37:43 on here you've got a whole role of negative charges. 419 00:37:43 --> 00:37:47 This is a molecule in which the various parts are not happy to be 420 00:37:47 --> 00:37:51 together because all these negative charges would like to push apart so 421 00:37:51 --> 00:37:55 when you break the bond of ATP then energy is released. 422 00:37:55 --> 00:37:59 So using ATP is a way of sort of storing chemical energy so you can 423 00:37:59 --> 00:38:03 use it in some other kind of context. 424 00:38:03 --> 00:38:09 And so by burning it, by carrying out the reaction in this 425 00:38:09 --> 00:38:16 way a cell is able to not only make a molecule of sugar, 426 00:38:16 --> 00:38:22 glucose into two lactate, it's able to generate ATP along the 427 00:38:22 --> 00:38:29 way. And the delta G prime zero for this reaction is minus 34 428 00:38:29 --> 00:38:35 kilocalories per mole. So even though it's taking out some 429 00:38:35 --> 00:38:41 of that energy and putting it in ATP, this is a reaction that goes very, 430 00:38:41 --> 00:38:47 very efficiently. Then instead of trying to carry out just that 431 00:38:47 --> 00:38:53 reaction, what the cell is actually doing is taking the two glutamate 432 00:38:53 --> 00:38:59 plus the two molecules of ammonia plus two ATP. 433 00:38:59 --> 00:39:05 And then this is converting it to two glutamine plus two water. 434 00:39:05 --> 00:39:12 I think I failed to put that in here so you can correct it back 435 00:39:12 --> 00:39:19 there. Plus two ADP plus two molecules of inorganic phosphate. 436 00:39:19 --> 00:39:26 And so the Pi very commonly used in biochemistry to denote just 437 00:39:26 --> 00:39:33 inorganic phosphate ion. So what's happen here then are these 438 00:39:33 --> 00:39:40 two reactions going on. This reaction now, because ATP is 439 00:39:40 --> 00:39:47 involved, is now favorable, and the delta G for this reaction is 440 00:39:47 --> 00:39:54 minus nine kilocalories per mole. So by having an ATP hydrolyzed as 441 00:39:54 --> 00:40:01 part of the reaction mechanism, this reaction that used to be 442 00:40:01 --> 00:40:09 unfavorable is now favorable. And then the kind of cute thing then 443 00:40:09 --> 00:40:17 is if you sum this all up, the ATPs and the ADPs are on both 444 00:40:17 --> 00:40:25 sides of the equation so they just drop out. And what you're left with 445 00:40:25 --> 00:40:33 is C6H12O6 plus the two glutamines plus two ammonias going to give two 446 00:40:33 --> 00:40:41 glutamines, excuse me, two lactate plus two glutamines plus 447 00:40:41 --> 00:40:49 the two waters. And the delta G prime zero for this 448 00:40:49 --> 00:40:57 is minus 43 kilocalories per mole. So this is not, you can think of it 449 00:40:57 --> 00:41:05 as using energy in the form of ATP like this a little the way we use 450 00:41:05 --> 00:41:11 money in our society. I do some work at MIT. 451 00:41:11 --> 00:41:15 I don't get given food to eat or TV to watch the Super Bowl. 452 00:41:15 --> 00:41:20 Instead I get given money, then I go to the store, I give them 453 00:41:20 --> 00:41:25 the money, I end up with the food or the stuff. And if you're watching 454 00:41:25 --> 00:41:29 it from the outside you see me do work at school and then food, 455 00:41:29 --> 00:41:34 TV or whatever shows up at home. But what's happening is the money is 456 00:41:34 --> 00:41:39 serving as a common intermediate in those transactions. 457 00:41:39 --> 00:41:44 And that's what basically ATP is in the cell. It's energy money. 458 00:41:44 --> 00:41:49 And in making ATP the cell has to take this ribose with an adenine on 459 00:41:49 --> 00:41:54 it, I think I didn't put the adenine on here I realize. 460 00:41:54 --> 00:42:00 The adenine is sitting on the ribose now. 461 00:42:00 --> 00:42:03 There are two phosphates, both of which have a negative charge 462 00:42:03 --> 00:42:07 on them. And to create that third bond it has to push it together. 463 00:42:07 --> 00:42:11 It's a very sort of an intrinsically unstable molecule. 464 00:42:11 --> 00:42:14 When you break the bond it will give you energy back. 465 00:42:14 --> 00:42:18 And that's one of the really amazing secretes to life, 466 00:42:18 --> 00:42:22 and that's the underlying principal of why it is that life can go 467 00:42:22 --> 00:42:26 forward. Now, the second issue that we need to 468 00:42:26 --> 00:42:37 quickly address here is -- 469 00:42:37 --> 00:42:41 -- not only can a reaction go, which is what thermodynamics tells 470 00:42:41 --> 00:42:46 us, but how can fast can it go. And this epitomizes the problem 471 00:42:46 --> 00:42:50 that all chemical reactions face because literally every chemical 472 00:42:50 --> 00:42:55 reaction that you carry out involves bringing a couple of 473 00:42:55 --> 00:43:00 entities together. And as they get closer and closer 474 00:43:00 --> 00:43:05 and closer they don't want to be there so you have to sort of push 475 00:43:05 --> 00:43:11 them together in some kind of way or make sure they have enough energy to 476 00:43:11 --> 00:43:16 get together. And that's what we see represented here. 477 00:43:16 --> 00:43:21 And that's a special term called the activation energy. 478 00:43:21 --> 00:43:27 It's given the term delta G with a double-dagger. And that is what -- 479 00:43:27 --> 00:43:31 It's the size of that activation energy that limits how fast chemical 480 00:43:31 --> 00:43:35 reactions can go. So the solution you use in 481 00:43:35 --> 00:43:39 chemistry, most of you, is you use a catalyst. And the 482 00:43:39 --> 00:43:43 catalyst doesn't change the outcome of the reaction. 483 00:43:43 --> 00:43:47 It just changes how fast you get there. So there are many reactions 484 00:43:47 --> 00:43:51 you've heard about in chemistry. Just stick the thing at 500 degrees 485 00:43:51 --> 00:43:55 centigrade, put in a piece of platinum, and now the reaction will 486 00:43:55 --> 00:43:58 go a whole lot faster. By heating it up molecules have more 487 00:43:58 --> 00:44:02 energy. So if they have more energy they can get closer together just 488 00:44:02 --> 00:44:06 from that. And then what the platinum surface would do is allow 489 00:44:06 --> 00:44:10 the molecules to both stick and that would bring them in proximately and 490 00:44:10 --> 00:44:14 also help them come together. Well, you cannot raise the 491 00:44:14 --> 00:44:18 temperature in a biological system, but still you have to overcome this. 492 00:44:18 --> 00:44:22 But the principal then, what you have to do when you carry out a 493 00:44:22 --> 00:44:26 catalyst, what any catalyst would do is that it lowers this 494 00:44:26 --> 00:44:41 activation energy. 495 00:44:41 --> 00:44:45 And if you lower the activation energy then enough of the molecules, 496 00:44:45 --> 00:44:49 just at whatever condition they're in will have enough energy to be 497 00:44:49 --> 00:44:53 able to go. It won't change the size of the drop. 498 00:44:53 --> 00:44:57 It just changes how fast you reach that final equilibrium. 499 00:44:57 --> 00:45:01 And there are two forms of biological -- 500 00:45:01 --> 00:45:06 Two molecules that are biological catalysts. 501 00:45:06 --> 00:45:16 One of the molecules you know is 502 00:45:16 --> 00:45:23 enzymes. Enzymes are made of a protein. We spent a bunch of time 503 00:45:23 --> 00:45:29 working at that. One of the things I showed you the 504 00:45:29 --> 00:45:33 very first day, this is a thing made by the anthrax 505 00:45:33 --> 00:45:37 bacterium, anthrax lethal factor. What it actually is, it's a protein 506 00:45:37 --> 00:45:42 and it's an enzyme that's able to catalyze the cleavage of certain 507 00:45:42 --> 00:45:46 peptide bonds in proteins in our body. And in particular it goes 508 00:45:46 --> 00:45:51 after molecules that are involved in signaling processes inside of cells. 509 00:45:51 --> 00:45:55 And if we don't have those then we die. More recently it was 510 00:45:55 --> 00:46:00 discovered that RNA can be a catalyst. 511 00:46:00 --> 00:46:04 And these are called, if you have an RNA that's a catalyst 512 00:46:04 --> 00:46:09 it's called a ribozyme. And these seemed pretty exotic for 513 00:46:09 --> 00:46:13 a little while they first discovered the idea that a piece of RNA could 514 00:46:13 --> 00:46:18 serve as a catalyst in a biological system, but it eventually turned out 515 00:46:18 --> 00:46:22 that the ribosome, which we'll talk about in some 516 00:46:22 --> 00:46:27 detail which is the protein synthesizing machinery that creates 517 00:46:27 --> 00:46:31 those peptide bonds between each of the amino acids to make 518 00:46:31 --> 00:46:36 the proteins. It's a big conglomeration of RNA 519 00:46:36 --> 00:46:40 shown in gray and a bunch of different proteins that are shown in 520 00:46:40 --> 00:46:45 yellow, but the actual formation of the peptide bond, 521 00:46:45 --> 00:46:49 the thing that makes all proteins is actually catalyzed by a piece of RNA. 522 00:46:49 --> 00:46:54 And so the ribosome is actually a ribozyme. And it's ironic that that 523 00:46:54 --> 00:46:58 sense that a piece of RNA is catalyzing the bond that makes 524 00:46:58 --> 00:47:03 proteins possible. So we'll finish this up and get in 525 00:47:03 --> 00:47:07 then to glycolysis which is the most evolutionary ancient of these 526 00:47:07 --> 00:47:10 energy-producing systems on Monday. OK?