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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.

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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

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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

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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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00:14:54,000 --> 00:15:04,000
It will only dissolve things that
have a very hydrophobic character.

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00:15:04,000 --> 00:15:17,000
Then there are some special cases.

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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

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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

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a hydroxyl group.
And that's important because that

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00:16:04,000 --> 00:16:09,000
allows for the formation of another
special type of bond that if you

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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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00:16:15,000 --> 00:16:20,000
polypeptide chain that has a
cysteine on it and they're close

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00:16:20,000 --> 00:16:25,000
together in space,
what can happen is you can form a

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00:16:25,000 --> 00:16:31,000
covalent bond between these under
oxidative conditions.

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00:16:31,000 --> 00:16:36,000
This is known as a disulfide bond.
That's covalent.

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00:16:36,000 --> 00:16:40,000
So those two chains,
if that bond occurs, are now sort of

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semi-permanently locked together.
They're locked together in a very,

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00:16:44,000 --> 00:16:48,000
very strong way.  So this is a
feature of, this is the only

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00:16:48,000 --> 00:16:53,000
intrastrand covalent bond that you'd
characteristically find in proteins.

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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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00:16:57,000 --> 00:17:01,000
3-dimensional space,
depend on other kinds of

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00:17:01,000 --> 00:17:06,000
interactions.
And finally there's one last case

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00:17:06,000 --> 00:17:12,000
which is proline.
And this one is a little different

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00:17:12,000 --> 00:17:17,000
because in the amino acid the side
chain bends around like this and

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00:17:17,000 --> 00:17:23,000
joins here.  So it's actually
forming a little circle here between

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00:17:23,000 --> 00:17:29,000
the nitrogen, the amino group and
the carboxyl group.

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00:17:29,000 --> 00:17:33,000
And the consequence of this is this
bond cannot rotate.

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00:17:33,000 --> 00:17:37,000
The bond that would normally be
able to rotate is not able to do

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00:17:37,000 --> 00:17:41,000
that.  And so this is sort of a
protein you find that when there are

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00:17:41,000 --> 00:17:45,000
some of these regular structures,
I'm going to show you in a minute,

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00:17:45,000 --> 00:17:49,000
like helices and things, this
protein won't,

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00:17:49,000 --> 00:17:53,000
this amino acid particularly won't
fit into those structures.

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00:17:53,000 --> 00:17:57,000
So you tend to, if nature wants to
interrupt a particular regular

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00:17:57,000 --> 00:18:01,000
structure that's coming,
it will often find a proline right

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00:18:01,000 --> 00:18:07,000
at that particular point.
OK.  So what we've talked about up

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00:18:07,000 --> 00:18:14,000
until now is sort of just the very,
very basic piece of protein

219
00:18:14,000 --> 00:18:27,000
structure.

220
00:18:27,000 --> 00:18:34,000
It's what called the primary
structure which is nothing more than

221
00:18:34,000 --> 00:18:41,000
the sequence of amino acids.
However, here's a little piece of

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00:18:41,000 --> 00:18:48,000
protein.  This is polyalanine.
And one thing you can sort of see

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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

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00:18:56,000 --> 00:19:02,000
confirmation.
And let's say this had 300 amino

225
00:19:02,000 --> 00:19:06,000
acids or something,
there are essentially an infinite

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00:19:06,000 --> 00:19:10,000
number of confirmations.
And so one of the real holy grails

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00:19:10,000 --> 00:19:14,000
still in biology is trying to
understand if you see the linear

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00:19:14,000 --> 00:19:18,000
sequence of an amino acid,
which we can now deduce, excuse me,

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00:19:18,000 --> 00:19:22,000
of a protein, of an amino.  If you
see the linear sequence of amino

230
00:19:22,000 --> 00:19:26,000
acids in a protein,
and we can deduce those from

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00:19:26,000 --> 00:19:30,000
analyzing genomes and so on,
how do we go from a thing that says

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00:19:30,000 --> 00:19:34,000
a tryptophan, a cysteine,
a serine, a serine, a threonine,

233
00:19:34,000 --> 00:19:38,000
whatever down the chain to finding
its 3-dimensional structure and

234
00:19:38,000 --> 00:19:43,000
ultimately its role?
And you can sort of hopefully get a

235
00:19:43,000 --> 00:19:48,000
sense from this of why it's
important.  So there are levels this

236
00:19:48,000 --> 00:19:52,000
goes.  The next level is what's
known as secondary structure.

237
00:19:52,000 --> 00:19:57,000
These are regions of local
secondary structure and they're

238
00:19:57,000 --> 00:20:01,000
determined by hydrogen bonds.
And I'll show you how these go in

239
00:20:01,000 --> 00:20:05,000
just a second.
And then you can think about

240
00:20:05,000 --> 00:20:09,000
proteins in the tertiary structure.
So what we've done and sort of

241
00:20:09,000 --> 00:20:13,000
taken a chain and then found out how
a little region might take up a

242
00:20:13,000 --> 00:20:17,000
particular, for example,
here's a portion that's in a helix.

243
00:20:17,000 --> 00:20:21,000
This is fairly rigid right now
because of the way it's held

244
00:20:21,000 --> 00:20:25,000
together.  And we'll then find maybe
another region like a beta sheet I'm

245
00:20:25,000 --> 00:20:29,000
going to show you in a minute.
Ultimately we have to figure out how

246
00:20:29,000 --> 00:20:33,000
all these units fold up into a
3-dimensional structure.

247
00:20:33,000 --> 00:20:38,000
And what we get there is called the
tertiary structure.

248
00:20:38,000 --> 00:20:42,000
And this has some other forces
we're going to talk about besides

249
00:20:42,000 --> 00:20:47,000
covalent bonds and hydrogen bonds
that determine that.

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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

251
00:20:51,000 --> 00:20:56,000
of roles in nature and they're not
all single proteins running around

252
00:20:56,000 --> 00:21:01,000
being an enzyme or something
like that.

253
00:21:01,000 --> 00:21:05,000
Many of them are parts of machines
so they're made to fit together in

254
00:21:05,000 --> 00:21:10,000
absolutely beautiful ways.
Some of them have, at this point,

255
00:21:10,000 --> 00:21:14,000
fifty-hundred parts that all go
together fitting shapes and

256
00:21:14,000 --> 00:21:19,000
interacting with these shapes on the
principles that we'll be talking

257
00:21:19,000 --> 00:21:24,000
about here, the different forces
that make things happen in nature.

258
00:21:24,000 --> 00:21:28,000
And so quaternary means the
structure when there's more than one

259
00:21:28,000 --> 00:21:36,000
polypeptide chain.

260
00:21:36,000 --> 00:21:41,000
So getting a handle on protein
structure was kind of a very

261
00:21:41,000 --> 00:21:46,000
important intractable problem for a
long time because it was just too

262
00:21:46,000 --> 00:21:51,000
hard a nut to crack,
but in the 1930s and 1940s x-ray

263
00:21:51,000 --> 00:21:57,000
crystallography started to come into
usage where basically you'd bounce

264
00:21:57,000 --> 00:22:01,000
x-rays off of a crystal.
And then they would refract and

265
00:22:01,000 --> 00:22:05,000
you'd see characteristic reflections.
And you could work backwards to

266
00:22:05,000 --> 00:22:09,000
figure out what the structure of the
crystal was.  This had been applied

267
00:22:09,000 --> 00:22:13,000
to minerals and a lot of structure,
but it hadn't been applied to

268
00:22:13,000 --> 00:22:17,000
proteins.  When people started to
look they found there were certain

269
00:22:17,000 --> 00:22:21,000
proteins that gave characteristic
reflections.  Carotin,

270
00:22:21,000 --> 00:22:25,000
for example.  Your hair gives a
characteristic reflection around 5.

271
00:22:25,000 --> 00:22:29,000
angstroms.  So that suggested that
there was a repeating unit somewhere

272
00:22:29,000 --> 00:22:33,000
in carotin that had this.
And, again, with artificial peptides

273
00:22:33,000 --> 00:22:37,000
sometimes they were able to see
these reflections.

274
00:22:37,000 --> 00:22:42,000
And so that was where things stood
for a while.  And then one of these

275
00:22:42,000 --> 00:22:46,000
secondary structures,
a very, very important one known as

276
00:22:46,000 --> 00:22:51,000
the alpha helix was deduced by Linus
Pauling.  Some of you have heard of

277
00:22:51,000 --> 00:22:55,000
him.  He was a famous chemistry at
Caltech.  He got the Nobel prize.

278
00:22:55,000 --> 00:23:00,000
He also got famous later in his
career because he championed the use

279
00:23:00,000 --> 00:23:04,000
of vitamin C to cure every ill known
to mankind, including

280
00:23:04,000 --> 00:23:09,000
the common cold.
Although there's some merit to what

281
00:23:09,000 --> 00:23:14,000
Linus stated, he probably overstated
some of those later findings,

282
00:23:14,000 --> 00:23:19,000
but his contributions to the
underlying chemistry and

283
00:23:19,000 --> 00:23:24,000
biochemistry of proteins was amazing.
And he was the one that figured out

284
00:23:24,000 --> 00:23:29,000
the structure that explained the 5.
angstrom repeat.

285
00:23:29,000 --> 00:23:33,000
And it was kind of an interesting
story.  He was in Oxford,

286
00:23:33,000 --> 00:23:38,000
England.  And he got sick.
I think it was some time in the

287
00:23:38,000 --> 00:23:42,000
winter.  And he got bored reading
detective books after a while so he

288
00:23:42,000 --> 00:23:47,000
thought he'd try and figure out the
structure of proteins that gave rise

289
00:23:47,000 --> 00:23:51,000
to this characteristic repeat.
So he made a simplifying assumption.

290
00:23:51,000 --> 00:23:56,000
He decided he'd forget all the side
chains and just focus on this

291
00:23:56,000 --> 00:24:01,000
peptide backbone just with
the peptide bond.

292
00:24:01,000 --> 00:24:06,000
And he was a chemist.
And he knew, what I just told you,

293
00:24:06,000 --> 00:24:11,000
that this had a partial double bond
character so it couldn't rotate.

294
00:24:11,000 --> 00:24:16,000
And he reasoned that this was held
together by, since these things

295
00:24:16,000 --> 00:24:21,000
could form hydrogen bonds that this
was probably forming a hydrogen bond

296
00:24:21,000 --> 00:24:26,000
with a carboxyl group of some other
amino acid and this was probably

297
00:24:26,000 --> 00:24:31,000
forming a hydrogen bond with an
amino group of a different

298
00:24:31,000 --> 00:24:40,000
amino acid.
And so what he did was he made a

299
00:24:40,000 --> 00:24:53,000
sort of chain like this and he
started to pleat it at the alpha

300
00:24:53,000 --> 00:25:06,000
carbon, which is the one that has
the side chain on it,

301
00:25:06,000 --> 00:25:19,000
and was finding to trying to
structure that would let him do this.

302
00:25:19,000 --> 00:25:32,000
And basically what he found was
that if he made a helix that looks

303
00:25:32,000 --> 00:25:45,000
something like this,
right-handed helix, and he could get

304
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

305
00:25:58,000 --> 00:25:53,000
And the repeating unit was 5.
angstroms and 3.7, excuse me,

306
00:25:53,000 --> 00:25:49,000
amino acids per turn.  And it's a
right-handed helix.

307
00:25:49,000 --> 00:25:44,000
It's the same sort of thing if
you're trying to turn in a screw.

308
00:25:44,000 --> 00:25:40,000
It's got that kind of structure.
And this shows you a little movie of

309
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,

310
00:25:35,000 --> 00:25:31,000
the backbone.  So this is the part
you can look right down

311
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

312
00:25:36,000 --> 00:25:40,000
thing into this regular structure.
And the neat thing about this then

313
00:25:50,000 --> 00:25:55,000
structure.  I think I can stop this.
I just want to show you one thing,

314
00:25:55,000 --> 00:26:00,000
if I can manage to this when it
comes around again.  Stop it there.

315
00:26:00,000 --> 00:26:03,000
One of the things you can see,
now we're looking down the helix.

316
00:26:03,000 --> 00:26:06,000
And although you won't recognize
the structures of all the amino

317
00:26:06,000 --> 00:26:10,000
acids right away,
you may be able to see in this

318
00:26:10,000 --> 00:26:13,000
particular one.
Here are a couple of aromatic rings

319
00:26:13,000 --> 00:26:17,000
off on this side.
So this side of the helix wouldn't

320
00:26:17,000 --> 00:26:20,000
like to see water,
and over here are a bunch of charged

321
00:26:20,000 --> 00:26:24,000
and polar amino acids.
So you could see how you could

322
00:26:24,000 --> 00:26:27,000
build into a helix like that,
a surface, one part that wouldn't

323
00:26:27,000 --> 00:26:31,000
like to interact with water and
another part that would.

324
00:26:31,000 --> 00:26:35,000
So that was an extremely important
contribution.  And there are alpha

325
00:26:35,000 --> 00:26:40,000
helices in almost all proteins.
They'll be in little chunks coming

326
00:26:40,000 --> 00:26:45,000
down an amino acids chain.
But they'll take up that structure.

327
00:26:45,000 --> 00:26:50,000
And, as you can see, it's driven by
these hydrogen bonds that we've been

328
00:26:50,000 --> 00:26:54,000
talking about.
There turns out then to be a second

329
00:26:54,000 --> 00:26:59,000
type of secondary structure that's
important.  It's called

330
00:26:59,000 --> 00:27:05,000
a beta sheet.
And in this case you can either line

331
00:27:05,000 --> 00:27:11,000
up two polypeptide chains running in
the same orientation,

332
00:27:11,000 --> 00:27:17,000
amino to carboxyl, amino to carboxyl,
or you can run them in opposite

333
00:27:17,000 --> 00:27:23,000
orientations, amino to carboxyl,
amino to carboxyl in the other way.

334
00:27:23,000 --> 00:27:29,000
The latter one is called an
anti-parallel beta sheet.

335
00:27:29,000 --> 00:27:34,000
And if you line things up this way
you'll see you can find hydrogen

336
00:27:34,000 --> 00:27:39,000
bonds between the chains like that.
So this allows two things to form

337
00:27:39,000 --> 00:27:44,000
in this way and gives a sort of
sheet-like structure.

338
00:27:44,000 --> 00:27:49,000
Whereas, that alpha helix has this
tight coil like this.

339
00:27:49,000 --> 00:27:54,000
So over here I think we have a
movie of a beta sheet.

340
00:27:54,000 --> 00:27:59,000
And you'll see again you can build
up more than one.

341
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

342
00:28:03,000 --> 00:28:08,000
more hydrogen bonds out in that kind
of way.  And, as I said,

343
00:28:08,000 --> 00:28:13,000
you can do this same trick putting
the polypeptide chains so they have

344
00:28:13,000 --> 00:28:17,000
the same polarity.
And so you can approximate,

345
00:28:17,000 --> 00:28:22,000
look at the structure of most
proteins then by depicting them

346
00:28:22,000 --> 00:28:27,000
either as alpha helices,
which you'll see in these diagrams.

347
00:28:27,000 --> 00:28:32,000
You've already seen a few in the
examples given.

348
00:28:32,000 --> 00:28:36,000
They'll look like this.
Or a beta sheet which are indicated

349
00:28:36,000 --> 00:28:40,000
as these flat arrows.
So here's a little piece of a

350
00:28:40,000 --> 00:28:44,000
protein made up of alpha helix,
these beta sheets.  What this is,

351
00:28:44,000 --> 00:28:49,000
actually, is a piece of the BRCA-1
gene.  That's the familial

352
00:28:49,000 --> 00:28:53,000
susceptibility to breast cancer.
The gene that causes that is called

353
00:28:53,000 --> 00:28:57,000
BRCA-1.  And it has a special
interaction domain called

354
00:28:57,000 --> 00:29:01,000
the BRC T domain.
This is the structure.

355
00:29:01,000 --> 00:29:05,000
And the only point I'm trying to
make, it's of a protein that's

356
00:29:05,000 --> 00:29:08,000
involved in preventing you from
getting breast cancer.

357
00:29:08,000 --> 00:29:12,000
If you get a mutation in it,
or particularly in this region,

358
00:29:12,000 --> 00:29:15,000
for example, you can end up with an
increased susceptibility to breast

359
00:29:15,000 --> 00:29:18,000
cancer.  But what is it?
It's an alpha helices beta sheet.

360
00:29:18,000 --> 00:29:22,000
There's green fluorescent protein.
You've seen that a few times.

361
00:29:22,000 --> 00:29:25,000
Maybe now you'll recognize it's
mostly made of beta sheets.

362
00:29:25,000 --> 00:29:29,000
There's a little bit of alpha helix
down there, a little

363
00:29:29,000 --> 00:29:32,000
bit right there.
And that has the property that we've

364
00:29:32,000 --> 00:29:36,000
talked about of fluorescing.
This is a protein I'll tell you

365
00:29:36,000 --> 00:29:40,000
later on that recognizes mismatches
in DNA, and you get a susceptibility

366
00:29:40,000 --> 00:29:44,000
to cancer if it breaks.
The only thing you notice here are

367
00:29:44,000 --> 00:29:47,000
a lot of alpha helices in it.
And hopefully already your eye can

368
00:29:47,000 --> 00:29:51,000
begin to pick these out.
This is an enzyme.  What it does is

369
00:29:51,000 --> 00:29:55,000
it's got a catalytic ability to
cleave other polypeptide chains.

370
00:29:55,000 --> 00:29:59,000
The functions of these don't matter.
But you can see once again alpha

371
00:29:59,000 --> 00:30:03,000
helices beta sheets.
Here's another one.

372
00:30:03,000 --> 00:30:07,000
It looks just about the same,
alpha helices, beta sheets, except

373
00:30:07,000 --> 00:30:12,000
in this case this is the human gene
known as, the protein encoded by

374
00:30:12,000 --> 00:30:16,000
human genes called RAS.
That's an oncogene.  That's a gene

375
00:30:16,000 --> 00:30:21,000
that if it mutates in a particular
way will cause the cell that has

376
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

377
00:30:26,000 --> 00:30:30,000
up a whole lot of structures that
have some alpha helices,

378
00:30:30,000 --> 00:30:35,000
some beta sheets.
But you can get the idea that you

379
00:30:35,000 --> 00:30:40,000
can get very, very different
biological activities from just

380
00:30:40,000 --> 00:30:45,000
depending on how you arrange those.
OK.  So there are a couple of other

381
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

382
00:30:50,000 --> 00:30:55,000
way to understanding the
3-dimensional structure of proteins.

383
00:30:55,000 --> 00:31:00,000
What we can get to from that is
alpha helices beta sheets.

384
00:31:00,000 --> 00:31:04,000
But you saw there were loops,
there were other interactions that I

385
00:31:04,000 --> 00:31:09,000
haven't accounted for in showing you
those 3-dimensional structures.

386
00:31:09,000 --> 00:31:14,000
So one of them are ionic bonds.
This is the third class of force.

387
00:31:14,000 --> 00:31:19,000
This is an extreme case of electron
sharing where one atom gets all of

388
00:31:19,000 --> 00:31:24,000
the electrons.
So aspartate, which I had up on the

389
00:31:24,000 --> 00:31:28,000
board, aspartic acid looks like that,
but under physiological conditions

390
00:31:28,000 --> 00:31:33,000
the oxygen will get all the
electrons and you'll have

391
00:31:33,000 --> 00:31:39,000
a hydrogen on it.
And a consequence of that then is

392
00:31:39,000 --> 00:31:45,000
that if you have a polypeptide chain
that over here has an aspartate and

393
00:31:45,000 --> 00:31:52,000
over here has a lysine,
which is the four methylene groups,

394
00:31:52,000 --> 00:31:59,000
and the positively charged thing
here, you can get an ionic bond

395
00:31:59,000 --> 00:32:05,000
between those two amino acids that
can be very far apart on

396
00:32:05,000 --> 00:32:12,000
the polypeptide chain.
There may be a lot of amino acids in

397
00:32:12,000 --> 00:32:18,000
between, but what they then do is
bring these two points together and

398
00:32:18,000 --> 00:32:24,000
hold them like that.
The next class of force is kind of

399
00:32:24,000 --> 00:32:30,000
tricky.  You may have heard of it in
chemistry.  It's referred to as van

400
00:32:30,000 --> 00:32:34,000
der Waals interaction.
And the basis of this,

401
00:32:34,000 --> 00:32:38,000
without going into it too much,
is even a nonpolar bond --

402
00:32:38,000 --> 00:32:48,000
-- can have a transient polarity.

403
00:32:48,000 --> 00:33:00,000
And this then induces --

404
00:33:00,000 --> 00:33:05,000
-- a transient polarity in a nearby
bond.  And it has to be a really

405
00:33:05,000 --> 00:33:11,000
nearby bond.  So about 0.
to 0.4 nanometers.  Remember,

406
00:33:11,000 --> 00:33:17,000
covalent bonds are roughly half that
distance or something.

407
00:33:17,000 --> 00:33:23,000
So it's got to be a very,
very close interaction.  It's weak.

408
00:33:23,000 --> 00:33:29,000
It's only one-third to one-quarter
of a hydrogen bond,

409
00:33:29,000 --> 00:33:35,000
which you may recall is about
one-twentieth of a covalent bond.

410
00:33:35,000 --> 00:33:38,000
But there can be many,
many of them if the surfaces fit

411
00:33:38,000 --> 00:33:42,000
together really,
really tightly.  So if you have a

412
00:33:42,000 --> 00:33:45,000
protein fold, so there's a surface
here, and then it folds up in such a

413
00:33:45,000 --> 00:33:49,000
way that there's a surface here,
then you can get a lot of van der

414
00:33:49,000 --> 00:33:52,000
Waals interactions down here.
Now, I've never had a really good

415
00:33:52,000 --> 00:33:56,000
way of explaining this.
But today, part of these activities

416
00:33:56,000 --> 00:34:00,000
of this Hughes Professorship,
I've set up some seminars on

417
00:34:00,000 --> 00:34:04,000
teaching.
And I've invited a guy from Berkley

418
00:34:04,000 --> 00:34:09,000
named Robert Full who is talking in
68.180 at 4:00 PM.

419
00:34:09,000 --> 00:34:14,000
And I borrowed some things from him
this morning.  And we're just going

420
00:34:14,000 --> 00:34:19,000
to take a quick tour because I want
to show you this.

421
00:34:19,000 --> 00:34:24,000
He works on, well,
he does a lot of things.

422
00:34:24,000 --> 00:34:30,000
He works on biomotion and how
animals work.

423
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

424
00:34:37,000 --> 00:34:44,000
go here.  Oops.
How do I figure out how to get it

425
00:34:44,000 --> 00:34:51,000
to play here?  Hang on a second.
I just discovered that the

426
00:34:51,000 --> 00:34:59,000
PowerPoint is not really
terribly effective.

427
00:34:59,000 --> 00:35:04,000
So this isn't working as nicely as I
would like.  OK.

428
00:35:04,000 --> 00:35:09,000
Let's try this.  Just a minute.
Where are we?  Here we go.  OK.

429
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,

430
00:35:15,000 --> 00:35:20,000
but he did an undergrad project
library studying geckos.

431
00:35:20,000 --> 00:35:26,000
And here this is a transparent
surface.  And he's studying how the

432
00:35:26,000 --> 00:35:30,000
geckos climb up and down the thing.
And they were making measurements.

433
00:35:30,000 --> 00:35:34,000
And they found they couldn't
account for why this was such an

434
00:35:34,000 --> 00:35:37,000
efficient organism.
It used much less energy than most

435
00:35:37,000 --> 00:35:41,000
things, so they started looking into
how it adhered to the surface.

436
00:35:41,000 --> 00:35:44,000
It can go up a vertical wall, as
you can see here.

437
00:35:44,000 --> 00:35:47,000
And so they were able to look
underneath and they could see,

438
00:35:47,000 --> 00:35:51,000
see how it sort of peels off the
surface?  And this was a robot that

439
00:35:51,000 --> 00:35:54,000
they eventually built that's not
using the same molecular bases but

440
00:35:54,000 --> 00:35:58,000
uses this peeling thing.
And they can get a robot that

441
00:35:58,000 --> 00:36:02,000
climbs up a wall.
But that's not what we're going to

442
00:36:02,000 --> 00:36:07,000
talk about here.
We're going to instead,

443
00:36:07,000 --> 00:36:12,000
I hope, go back to here.  And you
can see that all of the geckos have

444
00:36:12,000 --> 00:36:17,000
these sort of bizarre toes,
and so they started looking to see

445
00:36:17,000 --> 00:36:22,000
what the underlying principle of
this was.  And they saw it has these

446
00:36:22,000 --> 00:36:28,000
setae.  And they got looking in
greater detail and blew it up.

447
00:36:28,000 --> 00:36:33,000
And then they found that there were,
as they started looking there were

448
00:36:33,000 --> 00:36:38,000
these little hairs.
And that's a 900 fold magnification.

449
00:36:38,000 --> 00:36:43,000
And once they got looking in more
detail they found the ends were

450
00:36:43,000 --> 00:36:48,000
split so that they were,
the very ends are about 200

451
00:36:48,000 --> 00:36:53,000
nanometers roughly at the end of
this.  And so a gecko has about a

452
00:36:53,000 --> 00:36:59,000
billion of these on its feet.
And what it turns out it does --

453
00:36:59,000 --> 00:37:02,000
And just to see,
here's a human hair.

454
00:37:02,000 --> 00:37:06,000
You see how it splits down?
Now, this is made of keratin,

455
00:37:06,000 --> 00:37:10,000
the molecule I just mentioned that
was used, alpha helices,

456
00:37:10,000 --> 00:37:13,000
but it's very, very fine.
And what it can do, it can make van

457
00:37:13,000 --> 00:37:17,000
der Waals interactions.
This is an animal that sticks to

458
00:37:17,000 --> 00:37:21,000
the wall by van der Waals
interactions.  And the peeling away

459
00:37:21,000 --> 00:37:25,000
allows it to break those bonds.
But, as you can see, they're

460
00:37:25,000 --> 00:37:29,000
enormously important.
He's got here a micrograph.

461
00:37:29,000 --> 00:37:33,000
They're measuring the force,
and the force is just huge.  This is

462
00:37:33,000 --> 00:37:37,000
the end of the thing,
the frayed end sticking to a surface.

463
00:37:37,000 --> 00:37:42,000
And for those of you who didn't
think biology any relevance to you,

464
00:37:42,000 --> 00:37:46,000
Bob was telling me about this.  They
followed up, he's an engineer as

465
00:37:46,000 --> 00:37:51,000
well and builds interdisciplinary
teams, and they've measured this

466
00:37:51,000 --> 00:37:55,000
stuff.  But this is turning into
what appears to look like it's going

467
00:37:55,000 --> 00:38:00,000
to be a $30 to $50 billion industry
as all sorts of things are --

468
00:38:00,000 --> 00:38:04,000
They're beginning to realize it can
hold car parts together,

469
00:38:04,000 --> 00:38:08,000
it can go in space shuttles,
Post-it notes.  And here's a little

470
00:38:08,000 --> 00:38:12,000
Band-Aid they made.
They own the patent on this

471
00:38:12,000 --> 00:38:16,000
self-cleaning dry adhesive.
It doesn't have to be made out of

472
00:38:16,000 --> 00:38:20,000
gecko stuff.  It could be made out
of all sorts of things.

473
00:38:20,000 --> 00:38:25,000
But, anyway, here's an example of
where not only are van der Waals

474
00:38:25,000 --> 00:38:29,000
forces very important,
but where somebody who started a

475
00:38:29,000 --> 00:38:33,000
very simply aspect of biology
worrying about the efficiency of how

476
00:38:33,000 --> 00:38:37,000
geckos ran and pushed it all the way
down to the molecular level

477
00:38:37,000 --> 00:38:41,000
understood a principal that's going
to make somebody a very

478
00:38:41,000 --> 00:38:45,000
large amount of money.
OK.  The last,

479
00:38:45,000 --> 00:38:48,000
and if anybody wants to come,
he's an amazing speaker.  Perhaps

480
00:38:48,000 --> 00:38:52,000
one of the most exciting speakers
I've ever heard.

481
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

482
00:38:55,000 --> 00:39:00,000
stuff to show you then.  OK.
So the last force here,

483
00:39:00,000 --> 00:39:07,000
it's not really a force,
but what we'll call hydrophobic

484
00:39:07,000 --> 00:39:14,000
effects.  And what I mean by this is
that the principle of this is that

485
00:39:14,000 --> 00:39:22,000
amino acids that don't like to
interact with water, so --

486
00:39:22,000 --> 00:39:33,000
So hydrophobic amino acids.

487
00:39:33,000 --> 00:39:37,000
These are ones like lucien and
phenylalanine.

488
00:39:37,000 --> 00:39:41,000
Well, I showed you the water the
other day and how it was forming

489
00:39:41,000 --> 00:39:45,000
hydrogen bonds between the molecules.
So if you're going to stick another

490
00:39:45,000 --> 00:39:48,000
molecule in there,
you're going to break a bunch of

491
00:39:48,000 --> 00:39:52,000
bonds.  And if you're not charged or
polar you cannot make new bonds with

492
00:39:52,000 --> 00:39:56,000
the water.  And so what happens,
if you put these together, just like

493
00:39:56,000 --> 00:40:00,000
if you put oil together it will all
bundle up and it will minimize its

494
00:40:00,000 --> 00:40:04,000
interactions with water.
And that's what proteins do.

495
00:40:04,000 --> 00:40:08,000
Here's the structure of a protein
all folded up in 3-dimensional space.

496
00:40:08,000 --> 00:40:13,000
And you can see at the core of the
protein how there are these many

497
00:40:13,000 --> 00:40:17,000
hydrophobic amino acids that are
interacting.  And let me just,

498
00:40:17,000 --> 00:40:22,000
I'm going to close by showing you
one more little movie.

499
00:40:22,000 --> 00:40:26,000
And the new version of PowerPoint
doesn't do this well so I'm just

500
00:40:26,000 --> 00:40:31,000
going to get out of this
for a second here.

501
00:40:31,000 --> 00:40:39,000
This is a really cool movie I saw.

502
00:40:39,000 --> 00:40:47,000
I want to show you a DNA repair
protein sticking to a piece of helix.

503
00:40:47,000 --> 00:40:55,000
Can you hit the lights somebody
there?  So this is a lesion on a

504
00:40:55,000 --> 00:41:03,000
piece of, see the double
helix here?

505
00:41:03,000 --> 00:41:06,000
And what I especially liked about
this is this is sort of a Star Wars

506
00:41:06,000 --> 00:41:10,000
movie.  You're going to fly down the
major groove of a double helix.

507
00:41:10,000 --> 00:41:14,000
And you can see where this
particular protein folded up in

508
00:41:14,000 --> 00:41:18,000
3-dimensional space is reaching down
into that helix.

509
00:41:18,000 --> 00:41:22,000
So this is sort of putting together
the two things that I've been

510
00:41:22,000 --> 00:41:26,000
telling you about.
This blue is a DNA repair protein.

511
00:41:26,000 --> 00:41:30,000
Oopsy daisy.
A DNA repair protein that's able to

512
00:41:30,000 --> 00:41:34,000
find a lesion in the DNA.
And here's the double helix that's

513
00:41:34,000 --> 00:41:39,000
the two chains held together by
hydrogen bonds.

514
00:41:39,000 --> 00:41:43,000
And then, as you can see,
there's a groove on each side.

515
00:41:43,000 --> 00:41:46,000
And the protein is searching down
into that groove --