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So the big issue that I was trying
to take on yesterday,

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and this is of really fundamental
importance to biology,

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is that you saw from that molecular
composition of cells 80% water.

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Of the rest of it about 50% of
what's there by mass is protein.

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Proteins do most of the really
interesting stuff in the cell.

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They're the ones that are able to
catalyze specific chemical reactions

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with all this amazing chemistry
that's needed for life to take place

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at physiological conditions.
They are structural components of

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the cells.  They are all kinds of
amazing machines.

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I showed you the little flagellar
motor that turns it,

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but that's just one of many,
many nano machines that are

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necessary for life.
They have exquisite specificity

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when you get sick and you get an
immune response.

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You develop antibodies and other
cells that are able to recognize

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exactly some piece of that virus or
bacterium that has infected you and

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mount an immune response.
But all of the things that are doing

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that are proteins.
And the sort of, most of you I

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think know that,
as we've sort of said that amino

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acids are just a chain,
one amino acid joined to another

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amino acid to another amino
acid and so on.

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And so the backbone,
that peptide bond that I showed the

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other day is absolutely regular
piece of backbone.

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And what gives the amino acids
their character is the side chain

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that hangs off.
And you'll have different side

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chains hanging off depending on what
the amino acid is.

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And you will not have to memorize
all of those structures.

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But the important thing is that
these various amino acids fit into

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chemical categories that give them
properties.  They either have a plus

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charge and a negative charge,
they're hydrophobic, they don't like

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to go with water,
they are polar, they cannot interact

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with water and so on.
And it's clear from a couple of

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your comments,
some of you are why are we going

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through all of this?
Well, the reason we're going through

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all of this is all amino acids look
like this.  It doesn't matter.

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They're going to be an enzyme,
a part of a motor, a structural part

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of yourselves.
They all consist of the same

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backbone made up of those 20 amino
acids.  And what gives these,

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makes the proteins so important is
the ultimate 3-dimensional structure.

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I'm not sure what this sound is.
OK.  Let's try standing back here.

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What gives all of these proteins
their individual character is how

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this chain of amino acids,
you could just think of them like

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this, folds up into some
3-dimensional structure that

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ultimately is able to do the
biological function that we're

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trying to understand.
And one of the real holy grails

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still in biology is how to look at
the sequence of amino acids that

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constitute a protein and figure out
what the 3-dimensional

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structure is.
It's one of the holy grails that

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hasn't been solved.
One of you may have a key insight

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that will solve this.
If we could do that it would really

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be a huge advance,
because what you can get out of the

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genome sequences is you can read the
sequence of every gene and you can

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predict the sequence of amino acids
in the protein.

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But all it tells you is the linear
sequence of the amino acids.

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It doesn't tell you what the
3-dimensional structure is.

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And how an amino acid gets from the
sort of floppy chain linear

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structure to the 3-dimensional thing
is complicated.

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And you have to understand several
kinds of forces.

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And so I introduced a few terms.
When we think about protein

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structure, the primary structure,
that's just the linear sequence --

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-- of amino acids.

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So valine followed by a tryptophan,
followed by a proline, followed a

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threonine, whatever it would be.
That doesn't tell you very much.

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Then the first key part of
understanding how proteins get to a

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3-dimensional structure was the
discovery of what's termed

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secondary structure.

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And these are the thing I introduced
to you to the other day.

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There are two important ones.
An alpha helix and a beta sheet.

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And this is a propensity of a
certain string of amino acids in

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this linear sequence to adopt one of
two very common protein structures.

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And the important thing about these
elements, the alpha helices and the

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beta sheets is they are not
dependent on the side chain.

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So they are not.

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They are instead dependent
on hydrogen bonds --

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-- between N-H and the carbon double

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bond oxygen in the backbone.
And that was how Linus Pauling

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figured out originally the alpha
helix.  He decided to ignore all the

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side chains.  And he worked out that
you could arrange the backbone of a

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protein, the peptide bonds into
these repeating structures that

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would account for the reflections
he'd seen.  When we get to talking

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about how Watson and Crick worked
out the structure,

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that's how they started out, too.
They decided to ignore,

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if you will, the side chains,
which are the As and Gs and Cs and

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Ts, which turned out to be not a
productive way to go after the

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structure of DNA.
But, in any case,

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that was part of what Linus Pauling
did in working these out.

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And so those little movies I showed
you, this is an alpha helix.

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Now, what's been done in this
picture is all the side chains have

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been taken off.
And so you can look at this in your

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textbook, you'll see pictures,
but these hydrogen bonds are --

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The amino acid is just in this helix.
It's coiling around.

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And at regular intervals there's
the opportunity for forming a

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hydrogen bond.
And we can, with some success but

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certainly not certainty,
predict that a particular sequence

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of amino acids is going to form an
alpha helix.  And part of what

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that's based on is there are some
amino acids that don't fit easily

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into an alpha helix,
so they'll disrupt one if it ever

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tried to form.
So that's one of the elements of

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protein structure.
So what you might get from this is

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the idea that somewhere along here
this little piece of the linear

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sequence is apt to be an alpha helix.
And you can represent that as this

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little sort of coil that you see in
these 3-dimensional structures.

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The other one, which is the beta
sheet, now that involves

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interactions between two pieces of,
two stretches of amino acids.  Maybe

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there was a loop in between.
And then you can get interactions

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between them.  And that,
oops.  Let me just go, there's the

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beta sheet interaction.
Now, those are represented as

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arrows.  You know,
it takes two of them to go.

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So you've got to have, to represent
a beta sheet in a 3-dimensional

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structure you have to have two of
those broad arrows.

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And there was a question why were
there arrows on them?

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Well, one of the things,
I think you can see if you look at

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those backbones,
is that both nucleic acid and

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protein backbones,
there's a polarity.

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If you start in this direction,
the amino terminus, it's got a

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particular direction.
It's not symmetric.  If you come

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back the other way you find carboxyl,
amino, the alpha carbon.

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And you'll find it in the opposite
order if you come back the other way.

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So there's an inherent polarity.
The arrows aren't represented on

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here, but they are when you look at
it in 3-dimensions.

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And you can either form beta sheets
where the two strands have the same

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polarity or, if in a case like that
where they loop back,

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then of course if this one was
pointing in this direction as it

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goes through the loop then the
opposite strand will be pointing in

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the other polarity,
one going this way and one going

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that way.  So this part
is sort of helpful.

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You can make guesses that maybe this
part has a tendency over here to

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form a beta sheet,
but you still haven't gotten very

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far towards understanding how you
get to the 3-dimensional structure.

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And just by putting on and
superimposing some amino acids onto

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that alpha helix then you can see
what happens, that if you form an

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alpha helix what happens is all the
side chains stick out.

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And now I think you can see,
those of you who are engineers

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anyway, if you wanted to build
something you have a cylinder and

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you can stick amino acids out that
have particular chemical

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characteristics.
And depending on the

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characteristics of those amino acids,
whether they have charges on them or

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if they hate water or something,
that will influence what happens to

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that component of the protein
structure when it gets into a

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3-dimensional thing.
And, as I think I showed you the

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other day, when we caught it looking
down the end on this particular

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example, here are a couple of
aromatic amino acids right here,

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they're on the same side of the
helix and they would hate water.

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Whereas, some of the other amino
acids up here are ones that have

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charges so those would love water.
So what this would look like is a

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cylinder part of which hated water
and part of which loved water.

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And you might guess it folded up in
3-dimensional space.

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The part that hated water might
fold towards the inside

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of the protein.
And the part of the cylinder that

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loved water would face to the
outside.  So that's sort of the

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underlying principle.
So the rest of the other forces

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that we had to understand in order
to get to what's called the tertiary

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structure, this is the full 3D
structure, which we can now

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determine by a variety of methods.
X-ray crystallography of proteins

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is probably the most common.
The NMR, for example,

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can be used to derive a
3-dimensional structure as well.

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And the other forces then that go
into this are ionic forces.

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Someone seemed confused by this,
but if you have a plus charge on

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this part of an amino acid and a
minus charge here,

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if in 3-dimensional space the plus
charge got somewhere near the minus

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charge then that would
form an ionic bond.

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And I think most of you know enough
electricity and magnetism that

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wouldn't surprise you that those two
would be attracted.

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The one that I think that has been
harder to understand is van der

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Waals interactions that we talked
about the other day,

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which is tricky in the sense that
for this course you don't

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particularly really need to
understand the underlying

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chemistry.
But the principal of it is that if

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you have a nonpolar bond,
one that hasn't got any particular

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attraction to it,
gets very, very close to another one,

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then the transient fluctuations in
one induce something in the other

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one that makes them stick together.
And the whole point about this is

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if you get two molecular surfaces
that are very,

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very close together,
about, you know, many two times the

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length of a covalent bond or
something, then you can generate

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very powerful forces.
Because even though each individual

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interaction is weak,
about a quarter or a third of a

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hydrogen bond,
summing them up can make them very,

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very strong.  And so that's another
kind of force that's important when

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a linear molecule is trying to
figure out how in space it's going

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to fold up.  The point of the gecko
thing was it's only relatively

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recently been discovered that the
reason those lizards can stick to

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walls is they have sort of
incredible split ends.

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I noticed a couple of you came to
Bob Full's talk the other day and

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you got to hear the full treatment.
But because the hairs on their feet

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are so split they're very fine and
the molecules are able to make very

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close interactions,
van der Waals interactions with the

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surface.  And that's what's holding
the gecko to the wall.

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And there are just so many of them
that it can support a whole gecko.

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And that's what could be the basis
of, he said to me,

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a $30 to $50 billion adhesive
industry, a self-cleaning dry

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adhesive.  And it's not something
magic only the gecko hair will do.

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You can design synthetic molecules
that have the same property and are

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able to make these millions of van
der Waals interactions.

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So that's two of the other things.
And the final thing, which isn't

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really a force but goes into this,
is this hydrophobic effect.

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And that is that if we have things,
amino acids such as valine or

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something that doesn't like to mix
with water, then when the protein

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folds up, the things that don't like
to interact with water will kind of

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go together just the way if you put
a lot of oil in the water it will

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sort of pull together.
Because any time you have something

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that gets stuck in water,
it disrupts hydrogen bonds and

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that's energetically unfavorable.
So the things that hate water will

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tend to lump together.
And you're all used to seeing

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little drops of oil and stuff
floating around.

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And let me switch over to this
other thing now.

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So this was just showing you one of

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these protein chains that's folded
up into a 3-dimensional structure.

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This happens to be something with
an enzymatic activity.

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But the important thing for right
now is what's been colored in here

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are the amino acids that if you look
back on the list of amino acids and

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what categories are,
you'd see some of them are said to

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have hydrophobic side chains.
You can see quite strikingly how

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the amino acids in the interior part
of this protein have clustered

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together.  They don't like to
interact with water.

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They interact very well with each
other.  Just like you can mix butter

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and oil, they mix together
very well.

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And so that is another factor that
contributes to the 3-dimensional

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00:16:03,000 --> 00:16:07,000
structure of these proteins.
So understanding what proteins are

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all about means ultimately
understanding their 3-dimensional

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structure.  And,
as I say, a big unsolved problem

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right at the moment is how do you
get from a linear chain of amino

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acids to one of these 3-dimensional
structures?  And you can imagine

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00:16:25,000 --> 00:16:29,000
with 20 different side chains
there's an unbelievable number of

224
00:16:29,000 --> 00:16:34,000
combinations that you can make.
Yet almost every protein in nature

225
00:16:34,000 --> 00:16:38,000
has one unique or one or two or
something confirmations that takes

226
00:16:38,000 --> 00:16:43,000
out, out of all the kinds of things
that you could do.

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00:16:43,000 --> 00:16:48,000
And it's this combination of forces
that does that.

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00:16:48,000 --> 00:16:52,000
You know, let me just go back for
one second.  So the final thing that

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00:16:52,000 --> 00:16:57,000
ones talks about when you're talking
about proteins are quaternary

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00:16:57,000 --> 00:17:02,000
structure.
And what that means is when you have

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00:17:02,000 --> 00:17:07,000
more than one polypeptide chain,
so if we have two different proteins

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00:17:07,000 --> 00:17:13,000
that interact,
this is protein number one and this

233
00:17:13,000 --> 00:17:18,000
is protein number two,
then there has to be some sort of

234
00:17:18,000 --> 00:17:23,000
interaction between each of these
three dimensional structures in

235
00:17:23,000 --> 00:17:29,000
order for the proteins
to stick together.

236
00:17:29,000 --> 00:17:33,000
Something like that flagellar motor
that let's the bacteria swim,

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00:17:33,000 --> 00:17:37,000
has many, many parts, all of which
have to fit together just the same

238
00:17:37,000 --> 00:17:42,000
way all the different parts of an
engine have to fit together.

239
00:17:42,000 --> 00:17:46,000
Now this next little movie is just
a dimer.  It's actually a

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00:17:46,000 --> 00:17:50,000
heterodimer so it's made of two
proteins.  They're different but

241
00:17:50,000 --> 00:17:55,000
they've come together and they're
interaction.  So what you will first

242
00:17:55,000 --> 00:17:59,000
see is the 3-dimensional structure
of each protein showing the alpha

243
00:17:59,000 --> 00:18:04,000
helices, the beta sheets,
and nothing else is shown.

244
00:18:04,000 --> 00:18:07,000
The side chains aren't shown.
The molecular surfaces aren't shown.

245
00:18:07,000 --> 00:18:10,000
You can just see the backbone.
You'll see alpha helix a turn, some

246
00:18:10,000 --> 00:18:13,000
beta sheets, just the kind of stuff
you were seeing the other day.

247
00:18:13,000 --> 00:18:17,000
But you'll see that the two
proteins are together.

248
00:18:17,000 --> 00:18:20,000
And this is actually a movie made
by Tom Schwartz who's a

249
00:18:20,000 --> 00:18:23,000
crystallogram who just started on
our facility this fall in the

250
00:18:23,000 --> 00:18:26,000
biology department.
It's one of the proteins he studied.

251
00:18:26,000 --> 00:18:30,000
And then after that he rotates it
around so you can see it.

252
00:18:30,000 --> 00:18:33,000
After that he then puts on the side
chains and then traces the surface.

253
00:18:33,000 --> 00:18:37,000
So this is what they call the van
der Waals surface.

254
00:18:37,000 --> 00:18:41,000
So this is what the protein would
actually look like.

255
00:18:41,000 --> 00:18:45,000
And what I think you'll see from
this is how incredibly well the

256
00:18:45,000 --> 00:18:49,000
proteins fit together.
The theme I'll probably keep saying

257
00:18:49,000 --> 00:18:53,000
all the way through the course is
biology works from fitting shapes.

258
00:18:53,000 --> 00:18:57,000
And things have to work incredibly
well, and that's also why these van

259
00:18:57,000 --> 00:19:01,000
der Waals forces become
so important.

260
00:19:01,000 --> 00:19:04,000
Because evolution has ended up
making things that just go together

261
00:19:04,000 --> 00:19:07,000
just like a hand in a perfectly fit
glove.  That's the way most of these

262
00:19:07,000 --> 00:19:11,000
interactions are.
So watch this little movie.

263
00:19:11,000 --> 00:19:14,000
So the light blue is one of the
proteins.  There's an alpha helix.

264
00:19:14,000 --> 00:19:18,000
There are a lot of alpha helices in
this one.  And the purple one is the

265
00:19:18,000 --> 00:19:21,000
other protein.
And you can see that in between

266
00:19:21,000 --> 00:19:25,000
them there's an interface.
And so those must be interacting.

267
00:19:25,000 --> 00:19:29,000
But when he superimposes now all the
amino acids in the surface,

268
00:19:29,000 --> 00:19:33,000
now what he's going to do, he's
going to pull those apart so you can

269
00:19:33,000 --> 00:19:42,000
see where they were interacting.

270
00:19:42,000 --> 00:19:45,000
Do you get the idea now of how
beautifully these things have folded

271
00:19:45,000 --> 00:19:49,000
up in 3-dimensional space in
positions so that they can fit

272
00:19:49,000 --> 00:19:53,000
together and work together as a
machine?  Just the same way if you

273
00:19:53,000 --> 00:19:57,000
were building a machine and you
needed to have two parts that you

274
00:19:57,000 --> 00:20:01,000
had to join together you've got a
tool thing so that the surfaces go

275
00:20:01,000 --> 00:20:04,000
exactly together.
That's what nature does.

276
00:20:04,000 --> 00:20:08,000
That's also why I'm making such a
deal out of this 3-dimensioanl

277
00:20:08,000 --> 00:20:11,000
structure of proteins and how it got
there.  I could just say it gets

278
00:20:11,000 --> 00:20:14,000
there by magic,
but it doesn't.  It's determined by

279
00:20:14,000 --> 00:20:18,000
this set of forces.
And one of the things we cannot do

280
00:20:18,000 --> 00:20:21,000
at this point is predict.
Here's a linear sequence of amino

281
00:20:21,000 --> 00:20:24,000
acids.  Here's the 3D structure.
That would be a huge advance in

282
00:20:24,000 --> 00:20:28,000
biology if one of you guys could
figure out how to do that

283
00:20:28,000 --> 00:20:33,000
during your career.
OK.  So I just want to reiterate

284
00:20:33,000 --> 00:20:39,000
some of the things that proteins do
because we'll be talking about them

285
00:20:39,000 --> 00:20:45,000
as we go along.
One thing they do,

286
00:20:45,000 --> 00:20:51,000
they act as enzymes which are
catalysts for biological reactions

287
00:20:51,000 --> 00:20:57,000
that take place under physiological
conditions.  And we'll give you a

288
00:20:57,000 --> 00:21:03,000
lot of examples of those enzymes
starting very soon.

289
00:21:03,000 --> 00:21:07,000
They play structural roles.
Our hair, our fingernails are made

290
00:21:07,000 --> 00:21:12,000
of protein.  The hairs on the
gecko's feet are made of keratin

291
00:21:12,000 --> 00:21:16,000
which is the same stuff our hair is
made of, except they basically got a

292
00:21:16,000 --> 00:21:21,000
whole lot of split ends.
They're finer hairs to begin with

293
00:21:21,000 --> 00:21:26,000
and a lot of split ends.
And that's what makes these very,

294
00:21:26,000 --> 00:21:30,000
very fine things that can make van
der Waals interactions

295
00:21:30,000 --> 00:21:35,000
with surfaces.
They play roles in specificity.

296
00:21:35,000 --> 00:21:41,000
For example, I mentioned the
antibodies.  And we'll talk about

297
00:21:41,000 --> 00:21:47,000
the immune response in some detail
at the end of the course.

298
00:21:47,000 --> 00:21:52,000
And one of the really magic things
that we've come to understand in

299
00:21:52,000 --> 00:21:58,000
biology recently is how it is that
your body has this immune system

300
00:21:58,000 --> 00:22:04,000
that's able to recognize literally
any molecule, any molecule.

301
00:22:04,000 --> 00:22:08,000
It doesn't matter whether it is
existed or you and your PhD thesis

302
00:22:08,000 --> 00:22:12,000
in chemistry synthesize something
the world has never seen before,

303
00:22:12,000 --> 00:22:16,000
your immune system can create an
antibody or something that will very,

304
00:22:16,000 --> 00:22:21,000
very specifically recognize that
particular shape in just the same

305
00:22:21,000 --> 00:22:25,000
sort of way that you saw the shape
on that movie.

306
00:22:25,000 --> 00:22:29,000
And you might think you'd need to
code a zillion millions of DNA in

307
00:22:29,000 --> 00:22:34,000
order to do that.
But there's a trick using

308
00:22:34,000 --> 00:22:39,000
combinatorial functions and mutation
that lets your body do that.

309
00:22:39,000 --> 00:22:44,000
Another example, which I was
showing you, that can do all sorts

310
00:22:44,000 --> 00:22:49,000
of little motors and machines,
I showed you the bacteria swimming

311
00:22:49,000 --> 00:22:54,000
around.  These are just E.
coli.  And you cannot see the

312
00:22:54,000 --> 00:22:59,000
flagellar motors,
but you can see them buzzing around

313
00:22:59,000 --> 00:23:04,000
just under a cover slip.
Some of them are stuck to the cover

314
00:23:04,000 --> 00:23:08,000
slip.  There we go.
In this one, which was taken by

315
00:23:08,000 --> 00:23:12,000
Howard Burge who is a professor at
Harvard, I just took this off his

316
00:23:12,000 --> 00:23:16,000
website, you can see the bacteria
swimming by having these flagella

317
00:23:16,000 --> 00:23:20,000
which are basically like sort of
propellers more or less that they

318
00:23:20,000 --> 00:23:24,000
turn.  Here's one where he used the
strobe so you can get a little bit

319
00:23:24,000 --> 00:23:28,000
better view of it.
And I showed you this picture in

320
00:23:28,000 --> 00:23:32,000
the first lecture.
So that's the machine,

321
00:23:32,000 --> 00:23:36,000
but every single part of that
machine is made of a protein that's

322
00:23:36,000 --> 00:23:40,000
got a very certain 3-dimensional
space.  And we're going to start

323
00:23:40,000 --> 00:23:44,000
talking about energetics,
how does this cell get energy?

324
00:23:44,000 --> 00:23:47,000
And one of the things you might
wonder is if you were to design such

325
00:23:47,000 --> 00:23:51,000
a nano machine how would you power
it?  They exist.

326
00:23:51,000 --> 00:23:55,000
I mean it's here.
But that's why in part I'm going to

327
00:23:55,000 --> 00:23:59,000
start talking about energy and how
cells make energy,

328
00:23:59,000 --> 00:24:03,000
because this is one of the things
they have to do.

329
00:24:03,000 --> 00:24:06,000
And that was, as I said,
was an average electron micrograph

330
00:24:06,000 --> 00:24:10,000
of a lot of those motors.
So you can see that although,

331
00:24:10,000 --> 00:24:13,000
you know, that's the textbook thing,
the actual thing is pretty much the

332
00:24:13,000 --> 00:24:17,000
same shape.  This is not at a
resolution where you can make out

333
00:24:17,000 --> 00:24:20,000
the individual proteins that put it
together, but some of those are

334
00:24:20,000 --> 00:24:24,000
starting to be known in
3-dimensional detail.

335
00:24:24,000 --> 00:24:28,000
And I thought you might enjoy
seeing this just to convince you

336
00:24:28,000 --> 00:24:31,000
it's a motor.  In this thing,
what Howard Burge did was he stuck

337
00:24:31,000 --> 00:24:35,000
the propeller,
if you will, the flagellar to a

338
00:24:35,000 --> 00:24:38,000
cover slip using an antibody.
And then he let them do their thing.

339
00:24:38,000 --> 00:24:42,000
And normally they would be turning
the propeller and swimming,

340
00:24:42,000 --> 00:24:45,000
but if the propeller is attached the
same thing would happen if you held

341
00:24:45,000 --> 00:24:49,000
onto the propeller of a boat and
turned on the motor the boat would

342
00:24:49,000 --> 00:24:52,000
start twirling around.
And what you're seeing here is

343
00:24:52,000 --> 00:24:56,000
bacterial that are twirling around
because their flagellar

344
00:24:56,000 --> 00:25:00,000
are stuck on.
And those of you who are observant

345
00:25:00,000 --> 00:25:04,000
will notice even that they change
direction.  And that's part of the

346
00:25:04,000 --> 00:25:08,000
system that bacteria use so they can
swim towards a food source or away

347
00:25:08,000 --> 00:25:12,000
from another one.
OK.  Here's just something to let

348
00:25:12,000 --> 00:25:17,000
you think about it.
If anybody can figure this out send

349
00:25:17,000 --> 00:25:21,000
me an email.  Here's something else.
The phenomenon I'm going to show

350
00:25:21,000 --> 00:25:25,000
you is due to a protein made by a
soil bacterium called Pseudomonas

351
00:25:25,000 --> 00:25:30,000
syringae.  You don't
need to know that.

352
00:25:30,000 --> 00:25:34,000
It associated with plants.
And what you're going to see is a

353
00:25:34,000 --> 00:25:38,000
little movie made by a couple of
post-docs in my lab where they took

354
00:25:38,000 --> 00:25:42,000
pure water.  And if it's pure water
you can cool it below freezing.

355
00:25:42,000 --> 00:25:47,000
You can get it down to, I don't
know, minus eight degrees centigrade

356
00:25:47,000 --> 00:25:51,000
and it still will be a liquid,
even though you know water freezes

357
00:25:51,000 --> 00:25:55,000
at zero degrees centigrade.
And what it has to do in order to

358
00:25:55,000 --> 00:25:59,000
turn into ice,
somewhere you have to nucleate the

359
00:25:59,000 --> 00:26:04,000
formation of an ice crystal.
And once it goes,

360
00:26:04,000 --> 00:26:08,000
going.  So, anyway,
what you're going to see is some

361
00:26:08,000 --> 00:26:12,000
super- cooled water they've made.
You can see there is zero degrees

362
00:26:12,000 --> 00:26:16,000
there.  And this is Metchitaga,
one of the post-docs in my lab.

363
00:26:16,000 --> 00:26:20,000
That's the super-cooled water.
She's taking a little bit of

364
00:26:20,000 --> 00:26:24,000
culture of this Pseudomonas syringae,
and she's just going to put it in,

365
00:26:24,000 --> 00:26:29,000
give a little tiny squirt, a few
micro-liters into that water.

366
00:26:29,000 --> 00:26:33,000
Now it's going all cloudy.
And now you might wonder what's

367
00:26:33,000 --> 00:26:37,000
happening there.
But, as you'll discovery,

368
00:26:37,000 --> 00:26:41,000
what happened is that what was
liquid water is now ice.

369
00:26:41,000 --> 00:26:48,000
That is due to one protein that this

370
00:26:48,000 --> 00:26:52,000
bacterium makes and displays on its
surface.  And here's a controlled

371
00:26:52,000 --> 00:26:57,000
experiment.  This is putting in a
little bit of rhizobium meliloti,

372
00:26:57,000 --> 00:27:02,000
another soil organism, and the same
amount of bacteria.

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00:27:02,000 --> 00:27:09,000
It didn't happen.
OK.  So that's due to a protein

374
00:27:09,000 --> 00:27:17,000
that was on the surface of that
bacterium.  Anybody have any idea

375
00:27:17,000 --> 00:27:24,000
what that could do?
Send me an email.  OK.

376
00:27:24,000 --> 00:27:32,000
There's one last class of
[UNINTELLIGIBLE] macromolecule.

377
00:27:32,000 --> 00:27:36,000
Those are lipids.
These are a little different in the

378
00:27:36,000 --> 00:27:40,000
sense that this is not know a long
chain made by joining together

379
00:27:40,000 --> 00:27:44,000
subunits as you see with the
proteins and nucleic acids,

380
00:27:44,000 --> 00:27:49,000
but putting together the parts
necessary to make a lipid involve

381
00:27:49,000 --> 00:27:53,000
the same principle,
that you end up splitting out water

382
00:27:53,000 --> 00:27:58,000
molecules.  That's a theme you've
heard over and over again.

383
00:27:58,000 --> 00:28:03,000
And if we take three long chain,
three fatty acids, some number of

384
00:28:03,000 --> 00:28:10,000
carbons --

385
00:28:10,000 --> 00:28:25,000
Some number of carbons.

386
00:28:25,000 --> 00:28:33,000
Just some arbitrary number here.
And then we take a three carbon

387
00:28:33,000 --> 00:28:41,000
compound that has three hydroxyl
groups.  Now, this is not a

388
00:28:41,000 --> 00:28:48,000
carbohydrate because you'll notice
there's not a double bond oxygen as

389
00:28:48,000 --> 00:28:56,000
you saw in the carbohydrates.
It's actually an alcohol that's

390
00:28:56,000 --> 00:29:04,000
known as glycerol.
And if we split out water like this

391
00:29:04,000 --> 00:29:12,000
what you get is a fat,
something you're familiar with from

392
00:29:12,000 --> 00:29:20,000
beef fat.  Or if you get something
like olive oil,

393
00:29:20,000 --> 00:29:28,000
you've heard the term unsaturated
fats.

394
00:29:28,000 --> 00:29:32,000
Maybe you'll recall from the second
lecture that if we had a single

395
00:29:32,000 --> 00:29:36,000
covalent bond,
or if we had a double or a triple

396
00:29:36,000 --> 00:29:40,000
bond that was called an unsaturated
bond.  So if you have an unsaturated

397
00:29:40,000 --> 00:29:45,000
bond in here somewhere then you end
up with an unsaturated fat.

398
00:29:45,000 --> 00:29:49,000
And most of you know probably
something like beef fat is solid.

399
00:29:49,000 --> 00:29:53,000
If you put it in a refrigerator
something like peanut oil

400
00:29:53,000 --> 00:29:59,000
will stay liquid.
And that's because if you have just

401
00:29:59,000 --> 00:30:05,000
saturated side chains from this then
they pack together very tightly and

402
00:30:05,000 --> 00:30:11,000
they will form a solid.
If you put a double bond in then

403
00:30:11,000 --> 00:30:17,000
there's a kink in the backbone and
it's hard for these things to pack

404
00:30:17,000 --> 00:30:23,000
together.  And that's why they're
called unsaturated fats.

405
00:30:23,000 --> 00:30:29,000
Now, there's a very particular kind
of lipid that's of unbelievable

406
00:30:29,000 --> 00:30:35,000
importance in biology known
as a phospholipid.

407
00:30:35,000 --> 00:30:39,000
And the reason that's so important
is that that is the boundary that

408
00:30:39,000 --> 00:30:43,000
determines the outside of a cell.
So every cell, every organism

409
00:30:43,000 --> 00:30:47,000
either is a single cell or is made
up of multiple cells.

410
00:30:47,000 --> 00:30:51,000
And, as I said in the first lecture,
that one of the secrets to life is

411
00:30:51,000 --> 00:30:55,000
having a boundary that goes around
your insides it separates your

412
00:30:55,000 --> 00:31:00,000
insides from all the rest
of the universe.

413
00:31:00,000 --> 00:31:08,000
And the way these membranes,
as they're called, are made of is

414
00:31:08,000 --> 00:31:17,000
what's known as a phospholipid
bilayer.  And it's the same

415
00:31:17,000 --> 00:31:25,000
principle as before.
It uses a glycerol, except that one

416
00:31:25,000 --> 00:31:34,000
of the fatty acids is replaced by a
phosphate group that will have some

417
00:31:34,000 --> 00:31:44,000
kind decoration added onto it.
And the other will have fatty acids

418
00:31:44,000 --> 00:31:59,000
at the other two positions.

419
00:31:59,000 --> 00:32:04,000
Now, you'll notice by splitting out
water here, the kind of bond that we

420
00:32:04,000 --> 00:32:10,000
have created, the chemical name of
this is an ester bond.

421
00:32:10,000 --> 00:32:16,000
And if we wanted to break it we
could add water back across it.

422
00:32:16,000 --> 00:32:22,000
So what's important about this
molecule is this part of the

423
00:32:22,000 --> 00:32:28,000
molecule, if you will,
is water-loving because the very

424
00:32:28,000 --> 00:32:34,000
polar bonds here,
the oxygen here would have a

425
00:32:34,000 --> 00:32:40,000
negative charge under physiological
conditions.

426
00:32:40,000 --> 00:32:46,000
And this part is,
if you will, water-hating.

427
00:32:46,000 --> 00:32:52,000
So phospholipids are often
represented in the following way

428
00:32:52,000 --> 00:32:58,000
where this is the water-loving and
then this would be the water-hating

429
00:32:58,000 --> 00:33:05,000
part here.
And so if you take phospholipids and

430
00:33:05,000 --> 00:33:12,000
you just try and disperse them in
water, they spontaneously

431
00:33:12,000 --> 00:33:20,000
self-assemble into structures that
bring the water-loving parts

432
00:33:20,000 --> 00:33:27,000
together and the water-hating parts
together.  And by so doing this they

433
00:33:27,000 --> 00:33:35,000
form what's known as a
phospholipid bilayer.

434
00:33:35,000 --> 00:33:40,000
And that's what this membrane is
made of.  Membrane of bacterial cell,

435
00:33:40,000 --> 00:33:45,000
membrane of our cells virtually the
same thing.  It has the property

436
00:33:45,000 --> 00:33:50,000
that is not permeable to very much.
Water can get across a very limited

437
00:33:50,000 --> 00:33:56,000
number of other chemical compounds,
but most things cannot.

438
00:33:56,000 --> 00:34:00,000
And so, by having this membrane,
what the cell is able to do then is

439
00:34:00,000 --> 00:34:05,000
control who comes in and who comes
out.  And the way it does that is it

440
00:34:05,000 --> 00:34:09,000
has to put particular importers or
exporters imbedded in the membrane

441
00:34:09,000 --> 00:34:14,000
that can carry out those functions.
Because, as you would guess, any

442
00:34:14,000 --> 00:34:18,000
system would have to bring stuff in,
get rid of waste, you'd have to be

443
00:34:18,000 --> 00:34:23,000
able to go back and forth.
The things that do all those

444
00:34:23,000 --> 00:34:27,000
transports across the membrane are,
what kind of molecule do you think

445
00:34:27,000 --> 00:34:32,000
it likely to be?
If nature was going to design

446
00:34:32,000 --> 00:34:36,000
something that was a pump to get
something in or something that would

447
00:34:36,000 --> 00:34:41,000
get something out,
any idea what kind of molecule?

448
00:34:41,000 --> 00:34:46,000
Take a guess given what I've said
so far.  Protein.

449
00:34:46,000 --> 00:34:50,000
Yeah.  Absolutely.
And let me just sort of show you a

450
00:34:50,000 --> 00:34:55,000
couple little pictures here.
So here's a representation of this

451
00:34:55,000 --> 00:35:00,000
phospholipid bilayer.
This is pretty standard stuff.

452
00:35:00,000 --> 00:35:04,000
This is what you'd put on a
blackboard.  Here's in gray now the

453
00:35:04,000 --> 00:35:08,000
phospholipid.  And here's one of
these proteins,

454
00:35:08,000 --> 00:35:12,000
a picture of one of these proteins
that functions to get things across

455
00:35:12,000 --> 00:35:16,000
the membrane.  And hopefully what
you can see now is that it's made up

456
00:35:16,000 --> 00:35:20,000
of a whole lot of alpha helices,
and they pack together to give sort

457
00:35:20,000 --> 00:35:24,000
of a cylinder made up of different
alpha helices that weave in out like

458
00:35:24,000 --> 00:35:28,000
this.  And then by this sort of
trick the protein is able to create

459
00:35:28,000 --> 00:35:32,000
a channel that runs up and down the
middle of this protein that's

460
00:35:32,000 --> 00:35:36,000
imbedded in the membrane.
And then, depending on the

461
00:35:36,000 --> 00:35:40,000
characteristics that channel,
it can either be used to bring stuff

462
00:35:40,000 --> 00:35:44,000
in or get rid of it.
There is a more fanciful depiction

463
00:35:44,000 --> 00:35:48,000
of it.  This is not reality,
but there you are with the

464
00:35:48,000 --> 00:35:52,000
water-loving parts.
Here are the fatty acids going in.

465
00:35:52,000 --> 00:35:56,000
And this is supposed to be one of
these membrane proteins.

466
00:35:56,000 --> 00:36:00,000
Now, this next movie is trying to
pretend here that it's looking at

467
00:36:00,000 --> 00:36:04,000
one of these membrane proteins
colored here in red as it

468
00:36:04,000 --> 00:36:08,000
spans the membrane.
So here's looking from the membrane

469
00:36:08,000 --> 00:36:12,000
surface on.  And now it's going to
dive into this thing as it crossed

470
00:36:12,000 --> 00:36:16,000
the membrane.  And basically what
this movie is letting you do is feel

471
00:36:16,000 --> 00:36:20,000
like if you were the molecule that's
being transported across the

472
00:36:20,000 --> 00:36:24,000
membrane you'd see how you'd go
right down through a channel in the

473
00:36:24,000 --> 00:36:28,000
middle of the protein.
So that's one of the underlying

474
00:36:28,000 --> 00:36:32,000
principals then,
is that you have a phospholipid

475
00:36:32,000 --> 00:36:37,000
boundary that's critical for life.
But then to have everything else

476
00:36:37,000 --> 00:36:41,000
that needs to happen the cell makes
a series of proteins that function

477
00:36:41,000 --> 00:36:46,000
either to bring stuff in or to bring
it out.  Or in the case of something

478
00:36:46,000 --> 00:36:51,000
like the flagellar motor we talked
about it has to imbed a part of the

479
00:36:51,000 --> 00:36:55,000
machinery right in the membrane.
And one last picture I just want to

480
00:36:55,000 --> 00:37:00,000
show you.
Usually, even on that movie,

481
00:37:00,000 --> 00:37:04,000
you tend to see the cell represented
something like this with a membrane

482
00:37:04,000 --> 00:37:09,000
and every once in a while there's a
protein.  This is a cartoon but it

483
00:37:09,000 --> 00:37:13,000
is much closer to a to-scale drawing.
This is an E.

484
00:37:13,000 --> 00:37:18,000
coli cell.  Now,
they have an extra membrane that we

485
00:37:18,000 --> 00:37:23,000
won't worry about right for the
moment.  But right there,

486
00:37:23,000 --> 00:37:27,000
this little piece that we can see
little bits of, is the

487
00:37:27,000 --> 00:37:31,000
cell's membrane.
And what this picture is showing is

488
00:37:31,000 --> 00:37:35,000
that this membrane is just
absolutely studded with membrane

489
00:37:35,000 --> 00:37:38,000
proteins that are going to carry out
various functions.

490
00:37:38,000 --> 00:37:42,000
And here actually we're seeing that
motor which is imbedded both in the

491
00:37:42,000 --> 00:37:45,000
inner and outer membrane.
And there's the motor going off.

492
00:37:45,000 --> 00:37:49,000
But a couple of things maybe you
can take home from this is there are

493
00:37:49,000 --> 00:37:52,000
a lot of proteins stuck in those
membranes that control what goes in

494
00:37:52,000 --> 00:37:56,000
and out.  You also get a sense in
here of how crowded

495
00:37:56,000 --> 00:38:00,000
the cytoplasm is.
The proteins are really at amazingly

496
00:38:00,000 --> 00:38:06,000
high concentrations when they're
inside the cytoplasm.

497
00:38:06,000 --> 00:38:12,000
OK.  So that's sort of a quick
survey.  It's nothing more that a

498
00:38:12,000 --> 00:38:17,000
really superficial introduction to
the four classes of biomolecules.

499
00:38:17,000 --> 00:38:23,000
But to go any farther we're going
to have to think a little bit now

500
00:38:23,000 --> 00:38:29,000
about of the characteristics
of living cells.

501
00:38:29,000 --> 00:38:33,000
I don't know if any of you know if
any of you know what this is,

502
00:38:33,000 --> 00:38:38,000
but this is bakers yeast.  If you
were making bread you know you put

503
00:38:38,000 --> 00:38:43,000
some yeast in it and it divides and
it gives off carbon dioxide as a

504
00:38:43,000 --> 00:38:48,000
waste product and makes the bread
rise.  And what's happened in that

505
00:38:48,000 --> 00:38:52,000
little movie you just saw were two
cells dividing to give four,

506
00:38:52,000 --> 00:38:57,000
and four dividing to get eight,
and I don't know what we're up to

507
00:38:57,000 --> 00:39:02,000
here, but you can see a cell grow.
That's sped up.

508
00:39:02,000 --> 00:39:07,000
It takes probably something closer
to an hour for a cell division to

509
00:39:07,000 --> 00:39:12,000
take place.  But this is the kind of
thing that microorganisms do when

510
00:39:12,000 --> 00:39:18,000
they grow, is you can start with a
single cell and it will make two

511
00:39:18,000 --> 00:39:23,000
cells that are identical to itself
and those will make four.

512
00:39:23,000 --> 00:39:28,000
And what happens when we start out
as a single cell,

513
00:39:28,000 --> 00:39:32,000
we start out initially like this.
And we make cells that are identical

514
00:39:32,000 --> 00:39:36,000
at the beginning.
And those are the famous embryonic

515
00:39:36,000 --> 00:39:40,000
stem cells, because at this point
they can become any cell in your

516
00:39:40,000 --> 00:39:44,000
body.  And if you're a yeast it
doesn't matter.

517
00:39:44,000 --> 00:39:48,000
Everything you make is the same.
If it's a human, once you start

518
00:39:48,000 --> 00:39:52,000
dividing at some point cells are
going to have to start making

519
00:39:52,000 --> 00:39:56,000
decisions and the progeny will have
to start to be different of each

520
00:39:56,000 --> 00:40:00,000
other so that you can have something
that's an eye and another cell

521
00:40:00,000 --> 00:40:04,000
that's in the liver and so on.
And we'll talk a little bit about

522
00:40:04,000 --> 00:40:08,000
that as we go on.
But the major point,

523
00:40:08,000 --> 00:40:13,000
right at this point, is that all of
life involves one cell dividing and

524
00:40:13,000 --> 00:40:17,000
giving a couple of other cells,
and then those going on.  So these

525
00:40:17,000 --> 00:40:22,000
cells, as we've said,
characteristics of organisms which

526
00:40:22,000 --> 00:40:26,000
are to be true at their cellular
level as well is that they carry out

527
00:40:26,000 --> 00:40:31,000
metabolism, they undergo
regulated growth.

528
00:40:31,000 --> 00:40:36,000
And you have a nice example of yeast
undergoing regulated growth and they

529
00:40:36,000 --> 00:40:41,000
reproduce, which in the case of a
single-celled organism is the same

530
00:40:41,000 --> 00:40:46,000
as cell division.
For us reproducing is a lot more

531
00:40:46,000 --> 00:40:52,000
complicated because we have to make
a whole other multicellular organism

532
00:40:52,000 --> 00:40:57,000
where the cells have differentiated
functions, but the point about that

533
00:40:57,000 --> 00:41:03,000
is there has to be an unbelievable
amount of synthesis.

534
00:41:03,000 --> 00:41:07,000
The DNA in our body,
we start out with two meters in a

535
00:41:07,000 --> 00:41:11,000
fertilized cell,
and we have ten to the fourteenth

536
00:41:11,000 --> 00:41:16,000
cells by the time we're an adult.
So we've had to make a tremendous

537
00:41:16,000 --> 00:41:20,000
amount of DNA let alone protein and
everything else.

538
00:41:20,000 --> 00:41:25,000
And something almost all of you
know from your engineering

539
00:41:25,000 --> 00:41:29,000
background from this place is that
you need energy in order

540
00:41:29,000 --> 00:41:35,000
to synthesize material.
And what we'll start to talk about

541
00:41:35,000 --> 00:41:41,000
in the next phase of this course
then is how do cells make energy and

542
00:41:41,000 --> 00:41:47,000
how do they carry out metabolism.
So I'm going to, just before we do

543
00:41:47,000 --> 00:41:53,000
that, introduce to you very quickly,
to close out here, two classes of

544
00:41:53,000 --> 00:42:00,000
organisms that we find in nature.
We find organisms that are known as

545
00:42:00,000 --> 00:42:06,000
autotrophs.  These are certain
bacteria, and they're able to make

546
00:42:06,000 --> 00:42:13,000
everything they need starting with
CO2, ammonia, phosphate,

547
00:42:13,000 --> 00:42:20,000
water, a few things, but that's all
they need.  So,

548
00:42:20,000 --> 00:42:26,000
for example, an organism that lives,
a bacterium that lives out in the

549
00:42:26,000 --> 00:42:33,000
open ocean is able to make
everything from those very,

550
00:42:33,000 --> 00:42:43,000
very simple basic building blocks.
Heterotrophs need to eat --

551
00:42:43,000 --> 00:42:52,000
-- some things made by

552
00:42:52,000 --> 00:43:06,000
other organisms.

553
00:43:06,000 --> 00:43:09,000
An example of a heterotroph that
you're familiar with,

554
00:43:09,000 --> 00:43:13,000
that I'm familiar with is us.
You probably remember your mother

555
00:43:13,000 --> 00:43:17,000
reminding you,
as you're about to have yet another

556
00:43:17,000 --> 00:43:20,000
hotdog, that it was important to eat
your vitamins.

557
00:43:20,000 --> 00:43:24,000
The reason you need to eat vitamins,
those are things we absolutely need

558
00:43:24,000 --> 00:43:28,000
for our life but we cannot make them
ourselves.  Vitamin C is

559
00:43:28,000 --> 00:43:32,000
one you probably know.
It has an interesting history how

560
00:43:32,000 --> 00:43:36,000
people figured this out.
It was sailors at sea got really,

561
00:43:36,000 --> 00:43:40,000
really sick.  Their teeth would
start to loosen,

562
00:43:40,000 --> 00:43:44,000
they would start to bleed and they
would die.  Some of the famous sea

563
00:43:44,000 --> 00:43:48,000
voyages you heard about in high
school, I think the Cape of Good

564
00:43:48,000 --> 00:43:52,000
Hope, on that trip where that was
discovered 100 out of the 160

565
00:43:52,000 --> 00:43:56,000
sailors died at sea because of
scurvy.  Now, scurvy turns out to be

566
00:43:56,000 --> 00:44:00,000
due to not having vitamin C.
And there was finally a guy,

567
00:44:00,000 --> 00:44:04,000
Lind, I'm just blanking on his first
name at the moment,

568
00:44:04,000 --> 00:44:08,000
in about the 1700s who was a naval
surgeon in the British Navy who

569
00:44:08,000 --> 00:44:12,000
actually figured out that if you
gave sailors lemon juice that they

570
00:44:12,000 --> 00:44:17,000
didn't get scurvy.
It was a controlled experiment.

571
00:44:17,000 --> 00:44:21,000
It took about 50 years.  I think it
was 1795 when they started to

572
00:44:21,000 --> 00:44:25,000
finally give the sailors lemon juice
and stopped having this terrible

573
00:44:25,000 --> 00:44:29,000
sickness amongst their sailors.
And then in about 1950 they

574
00:44:29,000 --> 00:44:33,000
substituted lime juice.
And some of you may still know the

575
00:44:33,000 --> 00:44:37,000
British sailors are called ìlimeysî.
And that was because of this

576
00:44:37,000 --> 00:44:40,000
solution they found to avoiding
scurvy.  And what was really

577
00:44:40,000 --> 00:44:44,000
happening was they were finding a
way to provide vitamin C which is in

578
00:44:44,000 --> 00:44:48,000
fresh fruits and vegetables which
wasn't part of the classic sailor

579
00:44:48,000 --> 00:44:51,000
diet which was sort of biscuits and
dried meat during long voyages at

580
00:44:51,000 --> 00:44:55,000
sea.  And there are several other
vitamins, but the reason they're

581
00:44:55,000 --> 00:44:59,000
called vitamins is they're things
that you body cannot make but other

582
00:44:59,000 --> 00:45:05,000
organisms can.
The other thing that we cannot make,

583
00:45:05,000 --> 00:45:14,000
we can make some of our 20 amino
acids, but there are eight amino

584
00:45:14,000 --> 00:45:23,000
acids that we cannot make,
lysine, methionine, lucien,

585
00:45:23,000 --> 00:45:33,000
isoleucine, valine, threonine,
phenylalanine and tryptophan.

586
00:45:33,000 --> 00:45:38,000
And this actually has consequences
for us because those of you who are

587
00:45:38,000 --> 00:45:43,000
vegetarians probably know you have
to be kind of careful about your

588
00:45:43,000 --> 00:45:48,000
diet.  If you're eating animal
protein you're getting essentially

589
00:45:48,000 --> 00:45:53,000
all the different amino acids,
but if you're a vegetarian you have

590
00:45:53,000 --> 00:45:58,000
to be careful because the major food
crops such as wheat and rice,

591
00:45:58,000 --> 00:46:03,000
for example, are very low in lysine.

592
00:46:03,000 --> 00:46:07,000
So if you just eat those you end up
with a lysine deficiency that's not

593
00:46:07,000 --> 00:46:12,000
good.  But, on the other hand,
beans, lentils, the various

594
00:46:12,000 --> 00:46:17,000
leguminous plants,
which also are those ones that form

595
00:46:17,000 --> 00:46:21,000
the special associations with
bacteria that let them convert

596
00:46:21,000 --> 00:46:26,000
atmospheric nitrogen into ammonia,
legumes are high in lysine but low

597
00:46:26,000 --> 00:46:31,000
in methionine.
So peoples all over the world

598
00:46:31,000 --> 00:46:36,000
figured this out by trial and error.
So the Mexican diet is rice and

599
00:46:36,000 --> 00:46:41,000
beans.  There's a reason for it.
What's happening actually is just

600
00:46:41,000 --> 00:46:46,000
in the rice you're low in lysine,
but by having beans at the same time

601
00:46:46,000 --> 00:46:51,000
you're balancing out the two.
Or the Native Americans in this pat

602
00:46:51,000 --> 00:46:56,000
of the country had ìthe three
sistersî with the corn, the

603
00:46:56,000 --> 00:47:01,000
squash and the beans.
And again they were balancing out

604
00:47:01,000 --> 00:47:05,000
the diet by making sure that they
got the various amino acids,

605
00:47:05,000 --> 00:47:09,000
a balance of all the amino acids
that were necessary for life.

606
00:47:09,000 --> 00:47:13,000
It also actually was really good
gardening practice because the beans

607
00:47:13,000 --> 00:47:17,000
were able to convert atmospheric
nitrogen into ammonia,

608
00:47:17,000 --> 00:47:21,000
which was fertilizer, and the squash
leaves shaded the ground so that the

609
00:47:21,000 --> 00:47:25,000
ground didn't dry out,
and the corn could grow even when it

610
00:47:25,000 --> 00:47:30,000
was short on water.
But what was really happening,

611
00:47:30,000 --> 00:47:34,000
as people grew without even
understanding about chemistry,

612
00:47:34,000 --> 00:47:39,000
they were compensating for the fact
that we're heterotrophs and needed

613
00:47:39,000 --> 00:47:43,000
to do this.  So we'll start in the
next lecture on trying to talk about

614
00:47:43,000 --> 00:47:48,000
how cells make energy and how it
makes some of this amazing

615
00:47:48,000 --> 00:47:51,000
stuff happen.