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PROFESSOR: Let's check out some amino acids here, which have been provided
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to us right here.
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There are 20 flavors of amino acids--
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20 types of amino acids--
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because there are 20 different side chains.
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Now chemically, there could be more, but life has chosen to use 20, not 21,
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not 19, not any other number.
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It's chosen to use 20 amino acids, and those are incredibly important and
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they're worth getting to know.
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Now the first time you're going to meet 20 separate amino acids, you
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know, you don't want to remember them all as crazy different things.
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So let's group them together into important categories of amino acids.
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Let's see.
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We haven't written the C-alpha, C-O, H, or N-H, we haven't written this
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each time because that's the boring-- and the H over here-- because that's
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the boring part.
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Let's just put a blue dot there.
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The side chains.
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We've got a side chain here, CH2OH.
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Is that polar?
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Non-polar?
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Polar.
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Why's it polar?
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STUDENT: It's got the hydroxyl group.
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PROFESSOR: It's got the hydroxyl group there, so that's a polar bond.
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That can make polar bonds.
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That's good.
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So if this side chain is here, this side chain can make
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polar bonds very good.
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It can make hydrogen bonds.
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What about this guy here?
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How does threonine differ from serine?
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Well, it's again, that's C, here we go.
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Instead of just CH2OH, we've got an extra C over here.
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And still it's polar, nothing special, but it's a little bigger.
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Does that matter?
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Might matter.
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A little bigger might matter.
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What about over here?
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We've got an amino acid that's called asparagine, and it also is polar.
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And we've got glutamine, and it also is polar.
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But they're all different shapes and different sizes.
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But they're all polar.
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Now, all of these are polar, uncharged molecules.
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In this column, there are two amino acids which at neutral pH-- the body's
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pH of about pH 7--
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at neutral pH, these are negatively charged.
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Aspartic acid and glutamic acid are both negatively charged amino acids.
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At a different pH they might not be negatively charged, but at pH 7
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they're negatively charged.
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How do they differ?
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What's the difference between aspartic acid and glutamic acid?
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Can you see a difference between these two molecules?
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What's the difference?
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STUDENT: The extra CH2.
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PROFESSOR: Extra--
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the carbon chain here is one carbon longer.
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Pretty trivial, right?
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It's just a teeny bit longer.
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One extra carbon is not very long, but maybe that'll turn out to matter.
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And we'll come back and, in fact, we will see in the next lecture that that
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one extra carbon can make a huge difference in something working.
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So already I'm asking to anticipate that something as trivial as one extra
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carbon in length here can have a massive effect if in the right place.
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So we've got some negatives.
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There are two of them.
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We've also got some positives--
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lysine, arginine, and histidine.
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And these are positively charged at pH 7.
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OK?
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Positively charged.
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Positively charged.
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Positively charged.
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All right, so we've got polar uncharged, polar charged--
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polar positive, polar negative.
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You'll notice, every amino acid has a name.
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And because it's boring to write out threonine and glutamine all the time,
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it has a three letter code.
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Ser for serine.
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Thr here for threonine.
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Asparagine, Asn.
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And it has a one-letter code, as well.
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And some of the one-letter codes make enormous sense.
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Serine is S, and threonine is T, and asparagine is N because it's going to
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turn out another amino acid got the A already and asparagine had to settle
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for the N.
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And glutamine well, it turns out there's another amino acid who got the
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G. And you know, there's only 26 letters and 20 amino acids, and some
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poor amino acids have to settle for Q, right?
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There you go.
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So glutamine is Q. And the people who made up this code, it
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was reasonable choices.
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You know, histidine is an H, and arginine is an R because it's
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"AR-ginine," and things like that.
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OK?
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So it's the best you can.
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You should get to know these amino acids, at least basically the types of
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amino acids those are.
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Now how many have we got so far?
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One, two, three, four, five, six, seven, eight, nine so far.
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I owe you 11.
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OK.
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So let's go over here.
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We've got a bunch more amino acids.
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We've got hydrophobic amino acids.
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So far we've had polar bonds here, but now we're going to get to our nonpolar
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molecules here.
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Ah, where'd that A go?
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Instead of asparagine getting A, Alanine got the A. And
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let's see what we got.
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Again, we have our boring bit here.
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It's just CH3.
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No polar bonds there.
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It's hydrophobic.
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Valine--
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V. OK?
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We've got CH3s.
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No polar bonds here.
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No hydrogen bonding capability.
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Methionine is funny.
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What's methionine got that we haven't seen before?
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STUDENT: Sulfur.
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PROFESSOR: It's got a sulfur in the middle of it.
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That's very interesting.
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And there will be a time in the course that methionine having a sulfur will
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turn out to be really important, but that's many weeks away.
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But don't forget that methionine has a sulfur.
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Leucine--
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CH3, CH, CH3, CH2, you know, it's all just hydrocarbon.
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This is just some boring bit of hydrocarbon here and leucine and
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isoleucine.
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Why is this isoleucine and that's leucine?
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Because they are isomers of each other, right?
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It's basically the same thing, just rearranged in different ways.
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I have leucine.
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I have isoleucine.
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And then I have phenylalanine here.
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Phenylalanine has a ring structure here.
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So that's what I've got.
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I've also got tyrosine and tryptophan.
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And you're going to tell me there's an OH here.
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And it's a little bit polar, but it's mostly not.
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And so it gets classified here primarily as a hydrophobic amino acid.
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But it is true that there is one OH bond there, but it gets classified as
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hydrophobic.
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All right, so now we've got our polars.
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We've got uncharged polar, negative polar, positive.
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We've got our hydrophobics.
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They differ by shape.
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They differ by size within their classes.
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And they differ dramatically between the classes.
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We've got three more to go in understanding amino acids.
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Glycine.
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Glycine--
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that's where our G went, by the way--
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is just a measly hydrogen.
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It has no side chain to speak of at all, and therefore, it's an
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extraordinarily flexible amino acid.
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There's nothing that's really bumping into it, constraining it in any
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important way.
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By contrast, what we have here in proline is just the opposite.
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This is our alpha carbon here.
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Our alpha carbon has hanging off it a chain--
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CH2, CH2, CH2.
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This is a hydrophobic chain hanging off the alpha carbon.
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And what has it gone and done here?
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Instead of like every other amino acid sticking out into space like it's
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supposed to, it has come around and bonded with this nitrogen.
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That's the amino group that's not supposed to be
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playing any role, right?
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The side chain is supposed to be hanging off, and this side chain is
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not hanging off.
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This actually is not an amino acid.
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Technically, it is not an "amino" acid.
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It's an "imino" acid.
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Because the chemists distinguish between these things, this is
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technically not in an "amino" acid but an "imino" acid.
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I'm not going to care, and we're just going refer to all of them as "amino
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acids," and everybody refers to all of them as "amino acids." But
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nonetheless, you should know at least once.
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Now, because that's happened, whereas I said that glycine here was
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incredibly flexible, this guy is just the opposite.
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Because it's wrapped around and bonded back to that amino group there, it is
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constrained in the kinds of angles it can make.
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And so prolines act as interesting constraints on proteins.
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And finally, we have this one weird guy--
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cysteine.
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What's again unusual about a cysteine?
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Has our sulfur in it, but here the sulfur is at the end.
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And what happens is, if I have two cysteines pointing at each other,
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under many circumstances they can spontaneously make a covalent bond.
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So if in a long protein somewhere there's a cysteine sticking out, and
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somewhere else there's a cysteine sticking out, and they happen to come
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near each other, you can get a disulfide bond.
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All right.
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A disulfide bond.
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So now I told you the protein structure was incredibly
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straightforward.
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We have simply an amino acid, an amino acid, an amino acid.
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They get joined together.
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All we do is we make these peptide bonds here.
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They have some angles, and we have some different groups.
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That makes it sound really boring.
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But if I have a peptide--
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peptide means a short chain, a protein is a long chain--
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suppose I have a dipeptide, just two amino acids stuck together.
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How many options do I have?
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How many different dipeptides exist?
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Well, I've got 20 choices for the first one and 20 choices for the
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second one, so I have--
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STUDENTS: 400.
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PROFESSOR: 400 possible.
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How about tripeptides?
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8,000 possible.
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Tetrapeptides?
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Six--
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STUDENT: [INAUDIBLE].
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PROFESSOR: 160,000 tetrapeptides.
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Proteins can be hundreds of amino acids long.
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The number of options is huge.
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Let's just take a look at one for starters.
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Let's just look at a dipeptide for a second here.
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Here's a dipeptide.
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I just brought up a dipeptide and we're going to see how
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well this works here.
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Now, spin this guy around you see.
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Here we go.
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We've got arginine.
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Let's see.
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Pull this around like that.
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Why don't we do here--
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that's.
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Spinning it around.
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Come on.
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Oh, yeah.
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So what we've got here is the side chain for arginine hanging off.
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We've got the side chain of leucine hanging off.
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Arginine's side chain here.
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That's the R group.
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The side chain is in blue.
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The side chain here is in purple.
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And here is the backbone of the peptide here.
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OK?
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We've got--
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we'll move that a little bit so you can see it.
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Oh, yeah.
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There we go.
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It's hanging off the alpha carbon.
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Here's the carbon that has an oxygen, the carboxyl there that was there.
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Then it goes down here to the nitrogen.
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Then it goes to the alpha carbon off which is hanging that leucine.
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So let's take a look at this thing.
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What's striking is that peptide backbone we were talking about.
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It's pretty small compared to these side chains.
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The peptide backbone is the thread that's holding this all together.
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But those side chains can be pretty big, and they are very different in
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their chemical properties.
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All right.
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What does that mean?
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What does that mean for how proteins are going to fold up?
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Remember when we did something simple like how lipids fold?
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We were able to say, we're going to get all the hydrophobic bits, and
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we're going to put them together.
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We're going to put the hydrophilic bits and put them together.
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And they're going to make this beautiful, you know, lipid bilayer.
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Can you explain to me how we're going to fold up a protein?
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Suppose I give you a chain of 100 amino acids, and I'll tell you which
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ones they are.
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That's what I mean by the primary structure.
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The primary structure, arginine, leucine, methionine, tryptophan,
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histidine, et cetera.
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I'm going to give you a word of length 100 written in the
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language of amino acids.
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How are you going to fold it?
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Any proposals?
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Yeah?
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STUDENT: [INAUDIBLE].
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PROFESSOR: Sorry?
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STUDENT: Fold it back on itself.
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PROFESSOR: Fold it back on itself.
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Well, but what if, like, two positive charges end up near each other?
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STUDENT: Then you have to take something that's out of--
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PROFESSOR: So clearly, I don't want the positive charges next to each
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other, right?
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OK.
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What about the hydrophobics?
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Should they be nearer the polars?
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STUDENT: No.
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PROFESSOR: Now, let's get all the hydrophobics together.
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So we'll make a little convention of hydrophobics here.
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All the hydrophobics are all visiting together.
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We're trying to get the positives not by the positives, but positives by
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negatives sound pretty good.
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Of course, there's the cysteines.
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If two cysteines are near each other, they could make a disulfide--
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this starts getting complicated.
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This is actually very complicated.
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There's a zillion different in a peptide, in a protein of 100 amino
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acids long.
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There are a lot of ways to make these connections, to try to make a bridge
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between a positive and negative side chain, to try to organize the
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hydrophobics, to kind of be away from the solution away from the water, to
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the hydrophilics to be kind of pointing at the water.
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You might have to write a really complicated computer program to fold
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up a protein to best satisfy all of these somewhat conflicting rules.
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So that's called the "protein folding problem." The "protein folding
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problem" is incredibly easy to state.
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I give you the amino acids; you give me the structure.
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The "protein folding problem" remains, to this day, unsolved.
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No one can really write a computer program that just takes the sequence
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of an arbitrary protein and nail it as to exactly what structure
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it's going to form.
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Although folks are doing better and better and better with protein
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folding, it's not perfect.
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And it's because of two things.
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One, you've got to look at a whole bunch of funny combinations.
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There's lots and lots of alternatives.
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But there's one other thing-- that life makes it deliberately hard to
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fold a protein.
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And that's because the structures that proteins take up are right on the edge
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of stability.
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You might think, if I wanted to build a great protein I'm going
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to make it so rigid.
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I'm going to get lots of positives pointing at lots of negatives.
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I'm going to get everything arranged perfectly, and I'm going to get a
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structure which there's no alternative to it.
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It's going to be really nailed together, welded together, beautifully
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held by the laws of chemistry and physics.
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And the problem with that is it then is not very flexible.
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Proteins need to change.
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Proteins respond to their environments.
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They change in interesting ways.
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And the only way that's possible is if actually there is life on the edge.
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They're metastable.
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For people who think in terms of physics, they're not in some deep well
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that's hard to get out of.
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They're sitting right up here on the edge often easily perturbed in
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different ways.
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That's what makes the protein-folding hard.
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It's easy to give you a protein that wouldn't be hard to fold, but those
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tend not to be so interesting to life.
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All right, so boy, it seems to make your head hurt to think about how in
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the world you would ever fold a protein.
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Proteins fold by themselves.
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If I give you an amino acid sequence, and I toss it into the cytoplasm of
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the cell, it folds itself up.
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But it's how could you understand how it's going to
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resolve all those conflicts?
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All right, before going on, test yourself with two questions about
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amino acids.
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