WEBVTT

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So our next class of biomolecule
that we're going to talk about are

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nucleic acids.
And we can, for the most part,

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describe their properties by
considering just covalent bonds and

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hydrogen bonds.
Although, that's a bit of an

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oversimplification.
But, anyway, these are,

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again, polymers.
So this is DNA and RNA,

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terms you've undoubtedly heard.
And these are made by splitting out

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water.  And, in this case,
the monomeric units are given the

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special term nucleotide.
And a nucleotide consists of a

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sugar with something called
a base on it.

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It's got a phosphate group at one
end and a hydroxyl group,

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one of the sugar hydroxyls that we
saw the other day at the other end.

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The B stands for base.

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And the way the bond is formed,
as I said, is by splitting out water

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like that to form what's known as a
phosphodiester bond.

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And we'll be talking a lot about
those when we talk about DNA and RNA

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in more detail later on in the
course.  The sugars are pentoses

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where N equals 5.
We were talking about these the

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other day.  The base goes in this
position.  That's the 1 position

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of the carbon.
This is the 5 position of the carbon.

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And this is where the phosphate is
located.  This sugar is called

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ribose.  And then RNA,
which is the polymer of nucleotides

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that have ribose as the sugar is
ribonucleic acid or RNA,

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as you've known it.  If this
hydroxyl here is replaced by a

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hydrogen and the rest
of it's the same --

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-- this is deoxyribonucleoside.

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And if you polymerize that together
then you get DNA or deoxyribonucleic

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acid.
The bases come in two flavors.

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And this will be on your handout.
Ones that either have two rings,

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adenine or guanine.
And the general term of those is

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purine or they have one ring of
pyrimidine.  And in DNA one finds

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cytidine and thiamine abbreviated as
C and T.  Or in RNA,

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instead of finding thiamine you find
uracil, which is the same except

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that it doesn't have the methyl
group that's present at this

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position on thiamine.
And the important thing about these

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particular nucleotide bases is that
they can form hydrogen bonds in a

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very special way.
It's diagramed on here that this is

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a guanine pairing with the cytidine,
so a G pairing with a C.  And you

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can form three hydrogen bonds.
Or between an A, an adenine and a

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thiamine you can form
two hydrogen bonds.

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Those are just the things we were
diagramming on the board the other

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day.  And those are the forces that
hold the strands of DNA together so

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that DNA is the double helix,
as you know.  It's basically a

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backbone with sugars and phosphates.
And then there'll be some sequence

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of bases down this.
And then on the other strand you'll

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have the base that can form hydrogen
bonds with this.

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So C, there would be three hydrogen
bonds here.  This would be a G on

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this side, again,
three hydrogen bonds.

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If there's an A here that will be a
T there, two hydrogen bonds.

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And so on down.  And we'll talk
about the implications of this later

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in the course when we talk about DNA
replication, but for the moment I

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think your eye can see,
you can probably see that the

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geometric arrangement of these is
just exactly the same,

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whether it's a G-C or it's an A-T
base pair.  You can superimpose them,

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and they have just exactly the same
molecular structure.

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And that's really crucial for a lot
of things having to do with DNA.

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So, as you know, it's not just sort
of a ladder with hydrogen bonds.

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It's twisted in 3-dimensional space.
That's the double helix.

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And in that little movie I showed
you the nitrogen atoms and the bases

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are blue so you can pretty much pick
it out that there's a series of

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hydrogen bonds going right down the
middle of a DNA molecule with the

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phosphoribose backbone
on the outside.

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So every one of your cells,
since you have about 3 billion base

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pairs you have two point something
times that many hydrogen bonds

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holding your DNA together.
The thing to remember about the

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strength of the hydrogen bond,
it's about a twentieth a covalent

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bond, and so you're able to pull
those things apart and then put them

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back together at physiological
temperature while leaving all the

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covalent bonds that make up each
strand of the DNA leaving

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those intact.
It's also possible,

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since RNAs are usually
single-stranded,

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that if you have a little sequence
here that has the complimentary

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sequence over there then these can
pair like this forming a hairpin or

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some little structure like that.
And, again, we'll talk about

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transfer RNAs which play a really
key role in protein synthesis.

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They're the little translators that
go back and forth between the

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nucleic acid code,
the genetic code and the protein

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code, which is written
in amino acids.

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And this just shows making an RNA
copy for a tRNA gene from the DNA,

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but then these are the relationships
between the complimentary sequences

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right in that strand.
So this thing is able to fold up

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into a sort of cloverleaf structure
that some of you have certainly

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probably seen at some point.
It's a little bit twisted here

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because you can see how the
complimentary sequences

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have found each other.
And even though this is just a

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single strand of RNA,
by forming hydrogen bonds to

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complimentary sequences within
itself it can take up a structure.

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And I'll show you.  It actually
goes on, there are some other forces

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that come in.  And this will fold up
into a 3-dimensional structure that

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goes even beyond what I've shown you,
but we won't need to talk about that

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for just a little bit.  OK.
So then the next --

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-- class of molecules that we're

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going to spend a lot of this course
on are proteins.  And these

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are polymers again.

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-- made by splitting out water.
So that's been true of

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polysaccharides.
It's true of nucleic acids.

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It's true of proteins.  In this
case the monomers are structures

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known as amino acids.
And they have an amino group.

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And then it's joined to a carbon
known as the alpha carbon.

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And then there's a carboxyl group.
So this is why they're called amino

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acids, because their carboxyl
group is an acid.

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And the way they form --

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We'll give these different side
chains here.  I'll tell you about

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these side chains in just a minute.
The way these form a bond is by

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splitting out water here.
And then this will give this very

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important bond in nature --

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-- which is known as the peptide
bond.  And there's a chemical

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property of this that's important.
Someone was bemoaning the fact that

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I had to go over a bunch of
chemistry and they hadn't liked 5.

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11.  My apologies.
But we won't be spending all course

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doing chemistry.
But if you want to understand how

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these things work you do need to
understand some of the chemical

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principles to understand them.
And this is a case where it's

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really important because,
although it's written this way with

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the double bond here and a single
bond there, this double bond

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actually sort of spends part of its
time over here.

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So this is actually sort of a
partial double bond.

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And that has an important
consequence because if you're a

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single bond, if you remember a
single bond can bend and stretch but

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it can also rotate.
But if you're a double bond you

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cannot rotate.
So the peptide bond,

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and you make a lot of these when
you're polymerizing amino acids

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together to make proteins,
those bonds have a very special

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character that they cannot rotate.
Now, let me say, I'll come back and

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show you why that's important in
just a moment.

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But let me just say a word about
the side chains.

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There are 20 different amino acids.
And they have side chains that have

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very different chemical properties.
And when we start thinking about how

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a chain of amino acids take up the
properties that make it into an

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enzyme or part of a motor or a
structural protein or into your

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finger nails or your hair or skin,
they have to have very special

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properties.  And it's the sequence
of these different amino acids with

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their different chemical properties
that are eventually going to let

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each protein form up to one
particular 3-dimensional structure

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that will give it its
characteristics.

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So the different types of amino
acids, and again you won't have to

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memorize these,
but here they are up here.

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But let me just point out the
important classes,

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because the thing you really want to
do with this one is to remember the

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types of amino acids we find.
There are negatively charged amino

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acids.
An example of this would be

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aspartate.  Under physiological
conditions, although this is an acid,
it will dissociate so it will have a
negative charge.
And that's abbreviated as A-S-P.
Glutamine is another one that has a
negative charge.
There are also amino acids that
have positive charges
on the side chain.

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An example of this would be lysine
which has four methylene groups.

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And then it has an amino group.
But, again, under physiological

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conditions, around pH 7,
that will be protonated so it will

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have a plus charge.
And that is lysine or L-Y-S.

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And arginine and histidine are two
other amino acids that have a

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positive charge, or can have
a positive charge.

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Then there's a set of amino acids
that have a polar character.

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They don't have a full charge.
And, as you might guess, they have

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one of the bonds that we've talked
about that are polar.

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This is serine.

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Serine.  There's another one that
has a hydroxyl that's

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known as threonine.
And then there is a glutamine and

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asparagine, both of which have an
N-H bond.  So just through what I've

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told you here,
we haven't even been through the set,

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you can see how you can begin to
decorate an amino acid chain.

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So there's a plus charge and a
minus charge, a polar charge.

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There's a tremendous amount of
diversity because at every single

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thing you have a choice of 20 things
you can put in.

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So they not only have size and
shape characteristics,

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but they have particular charges and
other properties.

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Then, as always,
there are a bunch of special,

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oh, excuse me.  Actually, before we
do that, we have hydrophobic.

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Or you could think of these as

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greasy or water-hating.
These are the ones that are sort of

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when I was talking about trying to
dissolve butter into water.

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These are things that don't like to
interact with water or cannot

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interact with water,
and so they cannot form hydrogen

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bonds so you cannot get them to go
under water easily.

00:14:15.000 --> 00:14:20.000
And they come from very simple ones
that have just the methyl group

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which is alanine or A-L-A or one
like this which would be CH2-CH with

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a couple of methyl groups.
This is even more water-hating,

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that would be lucien, L-E-U.
Or here's one that you probably

00:14:34.000 --> 00:14:36.000
could guess that really doesn't
interact with water.

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This is phenylalanine or P-H-E.
And you can see what this side

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chain is.  It's a methylene group.
And what's dangling off it but a

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benzene ring.  And I think most of
you remember from probably beginning

00:14:44.000 --> 00:14:47.000
chemistry that benzene is something
that you cannot dissolve

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sugar in or something.
It's an organic solvent.

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It will only dissolve things that
have a very hydrophobic character.

00:15:04.000 --> 00:15:17.000
Then there are some special cases.

00:15:17.000 --> 00:15:21.000
Glycine is one,
because in this case the side chain

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is simply a hydrogen atom.
And, as a consequence to that,

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this is a very flexible amino acid.
So if you want to build --

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If nature wants to build a loop into
a protein, it's going to undergo a

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tight turn.  You often find glycines
there because there's not a big side

00:15:41.000 --> 00:15:47.000
chain to get in the way if you're
going to be bending the chain in

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3-dimensional space.
Another one is cysteine,

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which looks like serine over there,
but it has a thiol group instead of

00:15:59.000 --> 00:16:04.000
a hydroxyl group.
And that's important because that

00:16:04.000 --> 00:16:09.000
allows for the formation of another
special type of bond that if you

00:16:09.000 --> 00:16:15.000
have one chain of protein that has a
cysteine on it and another

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polypeptide chain that has a
cysteine on it and they're close

00:16:20.000 --> 00:16:25.000
together in space,
what can happen is you can form a

00:16:25.000 --> 00:16:31.000
covalent bond between these under
oxidative conditions.

00:16:31.000 --> 00:16:36.000
This is known as a disulfide bond.
That's covalent.

00:16:36.000 --> 00:16:40.000
So those two chains,
if that bond occurs, are now sort of

00:16:40.000 --> 00:16:44.000
semi-permanently locked together.
They're locked together in a very,

00:16:44.000 --> 00:16:48.000
very strong way.  So this is a
feature of, this is the only

00:16:48.000 --> 00:16:53.000
intrastrand covalent bond that you'd
characteristically find in proteins.

00:16:53.000 --> 00:16:57.000
All the rest of them we're going to
show you, when they fold up in

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3-dimensional space,
depend on other kinds of

00:17:01.000 --> 00:17:06.000
interactions.
And finally there's one last case

00:17:06.000 --> 00:17:12.000
which is proline.
And this one is a little different

00:17:12.000 --> 00:17:17.000
because in the amino acid the side
chain bends around like this and

00:17:17.000 --> 00:17:23.000
joins here.  So it's actually
forming a little circle here between

00:17:23.000 --> 00:17:29.000
the nitrogen, the amino group and
the carboxyl group.

00:17:29.000 --> 00:17:33.000
And the consequence of this is this
bond cannot rotate.

00:17:33.000 --> 00:17:37.000
The bond that would normally be
able to rotate is not able to do

00:17:37.000 --> 00:17:41.000
that.  And so this is sort of a
protein you find that when there are

00:17:41.000 --> 00:17:45.000
some of these regular structures,
I'm going to show you in a minute,

00:17:45.000 --> 00:17:49.000
like helices and things, this
protein won't,

00:17:49.000 --> 00:17:53.000
this amino acid particularly won't
fit into those structures.

00:17:53.000 --> 00:17:57.000
So you tend to, if nature wants to
interrupt a particular regular

00:17:57.000 --> 00:18:01.000
structure that's coming,
it will often find a proline right

00:18:01.000 --> 00:18:07.000
at that particular point.
OK.  So what we've talked about up

00:18:07.000 --> 00:18:14.000
until now is sort of just the very,
very basic piece of protein

00:18:14.000 --> 00:18:27.000
structure.

00:18:27.000 --> 00:18:34.000
It's what called the primary
structure which is nothing more than

00:18:34.000 --> 00:18:41.000
the sequence of amino acids.
However, here's a little piece of

00:18:41.000 --> 00:18:48.000
protein.  This is polyalanine.
And one thing you can sort of see

00:18:48.000 --> 00:18:56.000
is if I was trying to figure out how
to fold this up into a 3-dimensional

00:18:56.000 --> 00:19:02.000
confirmation.
And let's say this had 300 amino

00:19:02.000 --> 00:19:06.000
acids or something,
there are essentially an infinite

00:19:06.000 --> 00:19:10.000
number of confirmations.
And so one of the real holy grails

00:19:10.000 --> 00:19:14.000
still in biology is trying to
understand if you see the linear

00:19:14.000 --> 00:19:18.000
sequence of an amino acid,
which we can now deduce, excuse me,

00:19:18.000 --> 00:19:22.000
of a protein, of an amino.  If you
see the linear sequence of amino

00:19:22.000 --> 00:19:26.000
acids in a protein,
and we can deduce those from

00:19:26.000 --> 00:19:30.000
analyzing genomes and so on,
how do we go from a thing that says

00:19:30.000 --> 00:19:34.000
a tryptophan, a cysteine,
a serine, a serine, a threonine,

00:19:34.000 --> 00:19:38.000
whatever down the chain to finding
its 3-dimensional structure and

00:19:38.000 --> 00:19:43.000
ultimately its role?
And you can sort of hopefully get a

00:19:43.000 --> 00:19:48.000
sense from this of why it's
important.  So there are levels this

00:19:48.000 --> 00:19:52.000
goes.  The next level is what's
known as secondary structure.

00:19:52.000 --> 00:19:57.000
These are regions of local
secondary structure and they're

00:19:57.000 --> 00:20:01.000
determined by hydrogen bonds.
And I'll show you how these go in

00:20:01.000 --> 00:20:05.000
just a second.
And then you can think about

00:20:05.000 --> 00:20:09.000
proteins in the tertiary structure.
So what we've done and sort of

00:20:09.000 --> 00:20:13.000
taken a chain and then found out how
a little region might take up a

00:20:13.000 --> 00:20:17.000
particular, for example,
here's a portion that's in a helix.

00:20:17.000 --> 00:20:21.000
This is fairly rigid right now
because of the way it's held

00:20:21.000 --> 00:20:25.000
together.  And we'll then find maybe
another region like a beta sheet I'm

00:20:25.000 --> 00:20:29.000
going to show you in a minute.
Ultimately we have to figure out how

00:20:29.000 --> 00:20:33.000
all these units fold up into a
3-dimensional structure.

00:20:33.000 --> 00:20:38.000
And what we get there is called the
tertiary structure.

00:20:38.000 --> 00:20:42.000
And this has some other forces
we're going to talk about besides

00:20:42.000 --> 00:20:47.000
covalent bonds and hydrogen bonds
that determine that.

00:20:47.000 --> 00:20:51.000
And then, as I've tried to tell you,
you can see that proteins play a lot

00:20:51.000 --> 00:20:56.000
of roles in nature and they're not
all single proteins running around

00:20:56.000 --> 00:21:01.000
being an enzyme or something
like that.

00:21:01.000 --> 00:21:05.000
Many of them are parts of machines
so they're made to fit together in

00:21:05.000 --> 00:21:10.000
absolutely beautiful ways.
Some of them have, at this point,

00:21:10.000 --> 00:21:14.000
fifty-hundred parts that all go
together fitting shapes and

00:21:14.000 --> 00:21:19.000
interacting with these shapes on the
principles that we'll be talking

00:21:19.000 --> 00:21:24.000
about here, the different forces
that make things happen in nature.

00:21:24.000 --> 00:21:28.000
And so quaternary means the
structure when there's more than one

00:21:28.000 --> 00:21:36.000
polypeptide chain.

00:21:36.000 --> 00:21:41.000
So getting a handle on protein
structure was kind of a very

00:21:41.000 --> 00:21:46.000
important intractable problem for a
long time because it was just too

00:21:46.000 --> 00:21:51.000
hard a nut to crack,
but in the 1930s and 1940s x-ray

00:21:51.000 --> 00:21:57.000
crystallography started to come into
usage where basically you'd bounce

00:21:57.000 --> 00:22:01.000
x-rays off of a crystal.
And then they would refract and

00:22:01.000 --> 00:22:05.000
you'd see characteristic reflections.
And you could work backwards to

00:22:05.000 --> 00:22:09.000
figure out what the structure of the
crystal was.  This had been applied

00:22:09.000 --> 00:22:13.000
to minerals and a lot of structure,
but it hadn't been applied to

00:22:13.000 --> 00:22:17.000
proteins.  When people started to
look they found there were certain

00:22:17.000 --> 00:22:21.000
proteins that gave characteristic
reflections.  Carotin,

00:22:21.000 --> 00:22:25.000
for example.  Your hair gives a
characteristic reflection around 5.

00:22:25.000 --> 00:22:29.000
angstroms.  So that suggested that
there was a repeating unit somewhere

00:22:29.000 --> 00:22:33.000
in carotin that had this.
And, again, with artificial peptides

00:22:33.000 --> 00:22:37.000
sometimes they were able to see
these reflections.

00:22:37.000 --> 00:22:42.000
And so that was where things stood
for a while.  And then one of these

00:22:42.000 --> 00:22:46.000
secondary structures,
a very, very important one known as

00:22:46.000 --> 00:22:51.000
the alpha helix was deduced by Linus
Pauling.  Some of you have heard of

00:22:51.000 --> 00:22:55.000
him.  He was a famous chemistry at
Caltech.  He got the Nobel prize.

00:22:55.000 --> 00:23:00.000
He also got famous later in his
career because he championed the use

00:23:00.000 --> 00:23:04.000
of vitamin C to cure every ill known
to mankind, including

00:23:04.000 --> 00:23:09.000
the common cold.
Although there's some merit to what

00:23:09.000 --> 00:23:14.000
Linus stated, he probably overstated
some of those later findings,

00:23:14.000 --> 00:23:19.000
but his contributions to the
underlying chemistry and

00:23:19.000 --> 00:23:24.000
biochemistry of proteins was amazing.
And he was the one that figured out

00:23:24.000 --> 00:23:29.000
the structure that explained the 5.
angstrom repeat.

00:23:29.000 --> 00:23:33.000
And it was kind of an interesting
story.  He was in Oxford,

00:23:33.000 --> 00:23:38.000
England.  And he got sick.
I think it was some time in the

00:23:38.000 --> 00:23:42.000
winter.  And he got bored reading
detective books after a while so he

00:23:42.000 --> 00:23:47.000
thought he'd try and figure out the
structure of proteins that gave rise

00:23:47.000 --> 00:23:51.000
to this characteristic repeat.
So he made a simplifying assumption.

00:23:51.000 --> 00:23:56.000
He decided he'd forget all the side
chains and just focus on this

00:23:56.000 --> 00:24:01.000
peptide backbone just with
the peptide bond.

00:24:01.000 --> 00:24:06.000
And he was a chemist.
And he knew, what I just told you,

00:24:06.000 --> 00:24:11.000
that this had a partial double bond
character so it couldn't rotate.

00:24:11.000 --> 00:24:16.000
And he reasoned that this was held
together by, since these things

00:24:16.000 --> 00:24:21.000
could form hydrogen bonds that this
was probably forming a hydrogen bond

00:24:21.000 --> 00:24:26.000
with a carboxyl group of some other
amino acid and this was probably

00:24:26.000 --> 00:24:31.000
forming a hydrogen bond with an
amino group of a different

00:24:31.000 --> 00:24:40.000
amino acid.
And so what he did was he made a

00:24:40.000 --> 00:24:53.000
sort of chain like this and he
started to pleat it at the alpha

00:24:53.000 --> 00:25:06.000
carbon, which is the one that has
the side chain on it,

00:25:06.000 --> 00:25:19.000
and was finding to trying to
structure that would let him do this.

00:25:19.000 --> 00:25:32.000
And basically what he found was
that if he made a helix that looks

00:25:32.000 --> 00:25:45.000
something like this,
right-handed helix, and he could get

00:25:45.000 --> 00:25:58.000
a repeat structure that allowed him
to form a hydrogen bond.
you can build a tremendous amount of
diversity even within that helical

00:25:58.000 --> 00:25:53.000
And the repeating unit was 5.
angstroms and 3.7, excuse me,

00:25:53.000 --> 00:25:49.000
amino acids per turn.  And it's a
right-handed helix.

00:25:49.000 --> 00:25:44.000
It's the same sort of thing if
you're trying to turn in a screw.

00:25:44.000 --> 00:25:40.000
It's got that kind of structure.
And this shows you a little movie of

00:25:40.000 --> 00:25:35.000
an alpha helix.
You can see this is just showing
is if you put on the side chains,
and you can put them on in any order,

00:25:35.000 --> 00:25:31.000
the backbone.  So this is the part
you can look right down

00:25:31.000 --> 00:25:31.000
the end of it.
See how you can look right though?
And you can see how the hydrogen
bonds are formed by turning this

00:25:36.000 --> 00:25:40.000
thing into this regular structure.
And the neat thing about this then

00:25:50.000 --> 00:25:55.000
structure.  I think I can stop this.
I just want to show you one thing,

00:25:55.000 --> 00:26:00.000
if I can manage to this when it
comes around again.  Stop it there.

00:26:00.000 --> 00:26:03.000
One of the things you can see,
now we're looking down the helix.

00:26:03.000 --> 00:26:06.000
And although you won't recognize
the structures of all the amino

00:26:06.000 --> 00:26:10.000
acids right away,
you may be able to see in this

00:26:10.000 --> 00:26:13.000
particular one.
Here are a couple of aromatic rings

00:26:13.000 --> 00:26:17.000
off on this side.
So this side of the helix wouldn't

00:26:17.000 --> 00:26:20.000
like to see water,
and over here are a bunch of charged

00:26:20.000 --> 00:26:24.000
and polar amino acids.
So you could see how you could

00:26:24.000 --> 00:26:27.000
build into a helix like that,
a surface, one part that wouldn't

00:26:27.000 --> 00:26:31.000
like to interact with water and
another part that would.

00:26:31.000 --> 00:26:35.000
So that was an extremely important
contribution.  And there are alpha

00:26:35.000 --> 00:26:40.000
helices in almost all proteins.
They'll be in little chunks coming

00:26:40.000 --> 00:26:45.000
down an amino acids chain.
But they'll take up that structure.

00:26:45.000 --> 00:26:50.000
And, as you can see, it's driven by
these hydrogen bonds that we've been

00:26:50.000 --> 00:26:54.000
talking about.
There turns out then to be a second

00:26:54.000 --> 00:26:59.000
type of secondary structure that's
important.  It's called

00:26:59.000 --> 00:27:05.000
a beta sheet.
And in this case you can either line

00:27:05.000 --> 00:27:11.000
up two polypeptide chains running in
the same orientation,

00:27:11.000 --> 00:27:17.000
amino to carboxyl, amino to carboxyl,
or you can run them in opposite

00:27:17.000 --> 00:27:23.000
orientations, amino to carboxyl,
amino to carboxyl in the other way.

00:27:23.000 --> 00:27:29.000
The latter one is called an
anti-parallel beta sheet.

00:27:29.000 --> 00:27:34.000
And if you line things up this way
you'll see you can find hydrogen

00:27:34.000 --> 00:27:39.000
bonds between the chains like that.
So this allows two things to form

00:27:39.000 --> 00:27:44.000
in this way and gives a sort of
sheet-like structure.

00:27:44.000 --> 00:27:49.000
Whereas, that alpha helix has this
tight coil like this.

00:27:49.000 --> 00:27:54.000
So over here I think we have a
movie of a beta sheet.

00:27:54.000 --> 00:27:59.000
And you'll see again you can build
up more than one.

00:27:59.000 --> 00:28:03.000
Because if you look up here you can
see how you are all set up to form

00:28:03.000 --> 00:28:08.000
more hydrogen bonds out in that kind
of way.  And, as I said,

00:28:08.000 --> 00:28:13.000
you can do this same trick putting
the polypeptide chains so they have

00:28:13.000 --> 00:28:17.000
the same polarity.
And so you can approximate,

00:28:17.000 --> 00:28:22.000
look at the structure of most
proteins then by depicting them

00:28:22.000 --> 00:28:27.000
either as alpha helices,
which you'll see in these diagrams.

00:28:27.000 --> 00:28:32.000
You've already seen a few in the
examples given.

00:28:32.000 --> 00:28:36.000
They'll look like this.
Or a beta sheet which are indicated

00:28:36.000 --> 00:28:40.000
as these flat arrows.
So here's a little piece of a

00:28:40.000 --> 00:28:44.000
protein made up of alpha helix,
these beta sheets.  What this is,

00:28:44.000 --> 00:28:49.000
actually, is a piece of the BRCA-1
gene.  That's the familial

00:28:49.000 --> 00:28:53.000
susceptibility to breast cancer.
The gene that causes that is called

00:28:53.000 --> 00:28:57.000
BRCA-1.  And it has a special
interaction domain called

00:28:57.000 --> 00:29:01.000
the BRC T domain.
This is the structure.

00:29:01.000 --> 00:29:05.000
And the only point I'm trying to
make, it's of a protein that's

00:29:05.000 --> 00:29:08.000
involved in preventing you from
getting breast cancer.

00:29:08.000 --> 00:29:12.000
If you get a mutation in it,
or particularly in this region,

00:29:12.000 --> 00:29:15.000
for example, you can end up with an
increased susceptibility to breast

00:29:15.000 --> 00:29:18.000
cancer.  But what is it?
It's an alpha helices beta sheet.

00:29:18.000 --> 00:29:22.000
There's green fluorescent protein.
You've seen that a few times.

00:29:22.000 --> 00:29:25.000
Maybe now you'll recognize it's
mostly made of beta sheets.

00:29:25.000 --> 00:29:29.000
There's a little bit of alpha helix
down there, a little

00:29:29.000 --> 00:29:32.000
bit right there.
And that has the property that we've

00:29:32.000 --> 00:29:36.000
talked about of fluorescing.
This is a protein I'll tell you

00:29:36.000 --> 00:29:40.000
later on that recognizes mismatches
in DNA, and you get a susceptibility

00:29:40.000 --> 00:29:44.000
to cancer if it breaks.
The only thing you notice here are

00:29:44.000 --> 00:29:47.000
a lot of alpha helices in it.
And hopefully already your eye can

00:29:47.000 --> 00:29:51.000
begin to pick these out.
This is an enzyme.  What it does is

00:29:51.000 --> 00:29:55.000
it's got a catalytic ability to
cleave other polypeptide chains.

00:29:55.000 --> 00:29:59.000
The functions of these don't matter.
But you can see once again alpha

00:29:59.000 --> 00:30:03.000
helices beta sheets.
Here's another one.

00:30:03.000 --> 00:30:07.000
It looks just about the same,
alpha helices, beta sheets, except

00:30:07.000 --> 00:30:12.000
in this case this is the human gene
known as, the protein encoded by

00:30:12.000 --> 00:30:16.000
human genes called RAS.
That's an oncogene.  That's a gene

00:30:16.000 --> 00:30:21.000
that if it mutates in a particular
way will cause the cell that has

00:30:21.000 --> 00:30:26.000
that to move a step down the pathway
to cancer.  So what I've done is put

00:30:26.000 --> 00:30:30.000
up a whole lot of structures that
have some alpha helices,

00:30:30.000 --> 00:30:35.000
some beta sheets.
But you can get the idea that you

00:30:35.000 --> 00:30:40.000
can get very, very different
biological activities from just

00:30:40.000 --> 00:30:45.000
depending on how you arrange those.
OK.  So there are a couple of other

00:30:45.000 --> 00:30:50.000
then forces that I need to tell you
about if we're going to go all the

00:30:50.000 --> 00:30:55.000
way to understanding the
3-dimensional structure of proteins.

00:30:55.000 --> 00:31:00.000
What we can get to from that is
alpha helices beta sheets.

00:31:00.000 --> 00:31:04.000
But you saw there were loops,
there were other interactions that I

00:31:04.000 --> 00:31:09.000
haven't accounted for in showing you
those 3-dimensional structures.

00:31:09.000 --> 00:31:14.000
So one of them are ionic bonds.
This is the third class of force.

00:31:14.000 --> 00:31:19.000
This is an extreme case of electron
sharing where one atom gets all of

00:31:19.000 --> 00:31:24.000
the electrons.
So aspartate, which I had up on the

00:31:24.000 --> 00:31:28.000
board, aspartic acid looks like that,
but under physiological conditions

00:31:28.000 --> 00:31:33.000
the oxygen will get all the
electrons and you'll have

00:31:33.000 --> 00:31:39.000
a hydrogen on it.
And a consequence of that then is

00:31:39.000 --> 00:31:45.000
that if you have a polypeptide chain
that over here has an aspartate and

00:31:45.000 --> 00:31:52.000
over here has a lysine,
which is the four methylene groups,

00:31:52.000 --> 00:31:59.000
and the positively charged thing
here, you can get an ionic bond

00:31:59.000 --> 00:32:05.000
between those two amino acids that
can be very far apart on

00:32:05.000 --> 00:32:12.000
the polypeptide chain.
There may be a lot of amino acids in

00:32:12.000 --> 00:32:18.000
between, but what they then do is
bring these two points together and

00:32:18.000 --> 00:32:24.000
hold them like that.
The next class of force is kind of

00:32:24.000 --> 00:32:30.000
tricky.  You may have heard of it in
chemistry.  It's referred to as van

00:32:30.000 --> 00:32:34.000
der Waals interaction.
And the basis of this,

00:32:34.000 --> 00:32:38.000
without going into it too much,
is even a nonpolar bond --

00:32:38.000 --> 00:32:48.000
-- can have a transient polarity.

00:32:48.000 --> 00:33:00.000
And this then induces --

00:33:00.000 --> 00:33:05.000
-- a transient polarity in a nearby
bond.  And it has to be a really

00:33:05.000 --> 00:33:11.000
nearby bond.  So about 0.
to 0.4 nanometers.  Remember,

00:33:11.000 --> 00:33:17.000
covalent bonds are roughly half that
distance or something.

00:33:17.000 --> 00:33:23.000
So it's got to be a very,
very close interaction.  It's weak.

00:33:23.000 --> 00:33:29.000
It's only one-third to one-quarter
of a hydrogen bond,

00:33:29.000 --> 00:33:35.000
which you may recall is about
one-twentieth of a covalent bond.

00:33:35.000 --> 00:33:38.000
But there can be many,
many of them if the surfaces fit

00:33:38.000 --> 00:33:42.000
together really,
really tightly.  So if you have a

00:33:42.000 --> 00:33:45.000
protein fold, so there's a surface
here, and then it folds up in such a

00:33:45.000 --> 00:33:49.000
way that there's a surface here,
then you can get a lot of van der

00:33:49.000 --> 00:33:52.000
Waals interactions down here.
Now, I've never had a really good

00:33:52.000 --> 00:33:56.000
way of explaining this.
But today, part of these activities

00:33:56.000 --> 00:34:00.000
of this Hughes Professorship,
I've set up some seminars on

00:34:00.000 --> 00:34:04.000
teaching.
And I've invited a guy from Berkley

00:34:04.000 --> 00:34:09.000
named Robert Full who is talking in
68.180 at 4:00 PM.

00:34:09.000 --> 00:34:14.000
And I borrowed some things from him
this morning.  And we're just going

00:34:14.000 --> 00:34:19.000
to take a quick tour because I want
to show you this.

00:34:19.000 --> 00:34:24.000
He works on, well,
he does a lot of things.

00:34:24.000 --> 00:34:30.000
He works on biomotion and how
animals work.

00:34:30.000 --> 00:34:37.000
But one of the things he works on,
let's see if we can get this guy to

00:34:37.000 --> 00:34:44.000
go here.  Oops.
How do I figure out how to get it

00:34:44.000 --> 00:34:51.000
to play here?  Hang on a second.
I just discovered that the

00:34:51.000 --> 00:34:59.000
PowerPoint is not really
terribly effective.

00:34:59.000 --> 00:35:04.000
So this isn't working as nicely as I
would like.  OK.

00:35:04.000 --> 00:35:09.000
Let's try this.  Just a minute.
Where are we?  Here we go.  OK.

00:35:09.000 --> 00:35:15.000
Let's see if I can get this to go.
So he studies a bunch of things,

00:35:15.000 --> 00:35:20.000
but he did an undergrad project
library studying geckos.

00:35:20.000 --> 00:35:26.000
And here this is a transparent
surface.  And he's studying how the

00:35:26.000 --> 00:35:30.000
geckos climb up and down the thing.
And they were making measurements.

00:35:30.000 --> 00:35:34.000
And they found they couldn't
account for why this was such an

00:35:34.000 --> 00:35:37.000
efficient organism.
It used much less energy than most

00:35:37.000 --> 00:35:41.000
things, so they started looking into
how it adhered to the surface.

00:35:41.000 --> 00:35:44.000
It can go up a vertical wall, as
you can see here.

00:35:44.000 --> 00:35:47.000
And so they were able to look
underneath and they could see,

00:35:47.000 --> 00:35:51.000
see how it sort of peels off the
surface?  And this was a robot that

00:35:51.000 --> 00:35:54.000
they eventually built that's not
using the same molecular bases but

00:35:54.000 --> 00:35:58.000
uses this peeling thing.
And they can get a robot that

00:35:58.000 --> 00:36:02.000
climbs up a wall.
But that's not what we're going to

00:36:02.000 --> 00:36:07.000
talk about here.
We're going to instead,

00:36:07.000 --> 00:36:12.000
I hope, go back to here.  And you
can see that all of the geckos have

00:36:12.000 --> 00:36:17.000
these sort of bizarre toes,
and so they started looking to see

00:36:17.000 --> 00:36:22.000
what the underlying principle of
this was.  And they saw it has these

00:36:22.000 --> 00:36:28.000
setae.  And they got looking in
greater detail and blew it up.

00:36:28.000 --> 00:36:33.000
And then they found that there were,
as they started looking there were

00:36:33.000 --> 00:36:38.000
these little hairs.
And that's a 900 fold magnification.

00:36:38.000 --> 00:36:43.000
And once they got looking in more
detail they found the ends were

00:36:43.000 --> 00:36:48.000
split so that they were,
the very ends are about 200

00:36:48.000 --> 00:36:53.000
nanometers roughly at the end of
this.  And so a gecko has about a

00:36:53.000 --> 00:36:59.000
billion of these on its feet.
And what it turns out it does --

00:36:59.000 --> 00:37:02.000
And just to see,
here's a human hair.

00:37:02.000 --> 00:37:06.000
You see how it splits down?
Now, this is made of keratin,

00:37:06.000 --> 00:37:10.000
the molecule I just mentioned that
was used, alpha helices,

00:37:10.000 --> 00:37:13.000
but it's very, very fine.
And what it can do, it can make van

00:37:13.000 --> 00:37:17.000
der Waals interactions.
This is an animal that sticks to

00:37:17.000 --> 00:37:21.000
the wall by van der Waals
interactions.  And the peeling away

00:37:21.000 --> 00:37:25.000
allows it to break those bonds.
But, as you can see, they're

00:37:25.000 --> 00:37:29.000
enormously important.
He's got here a micrograph.

00:37:29.000 --> 00:37:33.000
They're measuring the force,
and the force is just huge.  This is

00:37:33.000 --> 00:37:37.000
the end of the thing,
the frayed end sticking to a surface.

00:37:37.000 --> 00:37:42.000
And for those of you who didn't
think biology any relevance to you,

00:37:42.000 --> 00:37:46.000
Bob was telling me about this.  They
followed up, he's an engineer as

00:37:46.000 --> 00:37:51.000
well and builds interdisciplinary
teams, and they've measured this

00:37:51.000 --> 00:37:55.000
stuff.  But this is turning into
what appears to look like it's going

00:37:55.000 --> 00:38:00.000
to be a $30 to $50 billion industry
as all sorts of things are --

00:38:00.000 --> 00:38:04.000
They're beginning to realize it can
hold car parts together,

00:38:04.000 --> 00:38:08.000
it can go in space shuttles,
Post-it notes.  And here's a little

00:38:08.000 --> 00:38:12.000
Band-Aid they made.
They own the patent on this

00:38:12.000 --> 00:38:16.000
self-cleaning dry adhesive.
It doesn't have to be made out of

00:38:16.000 --> 00:38:20.000
gecko stuff.  It could be made out
of all sorts of things.

00:38:20.000 --> 00:38:25.000
But, anyway, here's an example of
where not only are van der Waals

00:38:25.000 --> 00:38:29.000
forces very important,
but where somebody who started a

00:38:29.000 --> 00:38:33.000
very simply aspect of biology
worrying about the efficiency of how

00:38:33.000 --> 00:38:37.000
geckos ran and pushed it all the way
down to the molecular level

00:38:37.000 --> 00:38:41.000
understood a principal that's going
to make somebody a very

00:38:41.000 --> 00:38:45.000
large amount of money.
OK.  The last,

00:38:45.000 --> 00:38:48.000
and if anybody wants to come,
he's an amazing speaker.  Perhaps

00:38:48.000 --> 00:38:52.000
one of the most exciting speakers
I've ever heard.

00:38:52.000 --> 00:38:55.000
68-180, 4:00 PM if you want to go.
He'll have more of that sort of

00:38:55.000 --> 00:39:00.000
stuff to show you then.  OK.
So the last force here,

00:39:00.000 --> 00:39:07.000
it's not really a force,
but what we'll call hydrophobic

00:39:07.000 --> 00:39:14.000
effects.  And what I mean by this is
that the principle of this is that

00:39:14.000 --> 00:39:22.000
amino acids that don't like to
interact with water, so --

00:39:22.000 --> 00:39:33.000
So hydrophobic amino acids.

00:39:33.000 --> 00:39:37.000
These are ones like lucien and
phenylalanine.

00:39:37.000 --> 00:39:41.000
Well, I showed you the water the
other day and how it was forming

00:39:41.000 --> 00:39:45.000
hydrogen bonds between the molecules.
So if you're going to stick another

00:39:45.000 --> 00:39:48.000
molecule in there,
you're going to break a bunch of

00:39:48.000 --> 00:39:52.000
bonds.  And if you're not charged or
polar you cannot make new bonds with

00:39:52.000 --> 00:39:56.000
the water.  And so what happens,
if you put these together, just like

00:39:56.000 --> 00:40:00.000
if you put oil together it will all
bundle up and it will minimize its

00:40:00.000 --> 00:40:04.000
interactions with water.
And that's what proteins do.

00:40:04.000 --> 00:40:08.000
Here's the structure of a protein
all folded up in 3-dimensional space.

00:40:08.000 --> 00:40:13.000
And you can see at the core of the
protein how there are these many

00:40:13.000 --> 00:40:17.000
hydrophobic amino acids that are
interacting.  And let me just,

00:40:17.000 --> 00:40:22.000
I'm going to close by showing you
one more little movie.

00:40:22.000 --> 00:40:26.000
And the new version of PowerPoint
doesn't do this well so I'm just

00:40:26.000 --> 00:40:31.000
going to get out of this
for a second here.

00:40:31.000 --> 00:40:39.000
This is a really cool movie I saw.

00:40:39.000 --> 00:40:47.000
I want to show you a DNA repair
protein sticking to a piece of helix.

00:40:47.000 --> 00:40:55.000
Can you hit the lights somebody
there?  So this is a lesion on a

00:40:55.000 --> 00:41:03.000
piece of, see the double
helix here?

00:41:03.000 --> 00:41:06.000
And what I especially liked about
this is this is sort of a Star Wars

00:41:06.000 --> 00:41:10.000
movie.  You're going to fly down the
major groove of a double helix.

00:41:10.000 --> 00:41:14.000
And you can see where this
particular protein folded up in

00:41:14.000 --> 00:41:18.000
3-dimensional space is reaching down
into that helix.

00:41:18.000 --> 00:41:22.000
So this is sort of putting together
the two things that I've been

00:41:22.000 --> 00:41:26.000
telling you about.
This blue is a DNA repair protein.

00:41:26.000 --> 00:41:30.000
Oopsy daisy.
A DNA repair protein that's able to

00:41:30.000 --> 00:41:34.000
find a lesion in the DNA.
And here's the double helix that's

00:41:34.000 --> 00:41:39.000
the two chains held together by
hydrogen bonds.

00:41:39.000 --> 00:41:43.000
And then, as you can see,
there's a groove on each side.

00:41:43.000 --> 00:41:46.000
And the protein is searching down
into that groove --