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[Music]

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so what I'm gonna talk to you about I'm

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Martin

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I'm from the HUD lab and we're part of

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the Center for chemical evolution and

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beyond that were in I'm in the proto

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polypeptide team so like I work with

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Aaron McKie who talked a little bit

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earlier and so what I'm gonna talk about

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today is a problem in prebiotic

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chemistry and and I'm going to talk

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about how we are on how we think we're

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gonna be able to explore a solution to

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this problem some of the work that we've

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been doing so as you heard in in the

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first talk today by our Nobel laureate

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you can make biopolymers okay and so in

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this diagram here what I have I have

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just general any any kind of monomer you

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want to imagine can be these and biology

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today and nature as we know it it will

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take these monomers and it will assemble

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them it will stitch them together into

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some type of polymer okay and so

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importantly though is that what nature

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does is it stitches these in in a very

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specific order okay and then once once

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these monomers are stitched together in

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a specific order then usually what

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happens is these are able to fold in

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some way or function in some catalytic

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ways so you know the example I have here

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is these these monomers are all stitched

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together in a polymer and here they are

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folded together interacting with this

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cool little helix guy you know some

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interaction you know it could be it

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could be anything could be binding

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stabilizing interaction for example

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however if we try to think about

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prebiotic chemistry and you know the

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early Earth billions of years ago

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billions and billions of years ago we

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didn't have enzymes so if you didn't

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have enzymes and and if you didn't have

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templating mechanisms like a genetic

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coding system then how could you have

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reliably produced a functional sequence

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over and over again that could have led

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to biology or biology like processes so

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if

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we had a random pool of monomers on the

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prebiotic er with no enzymes nothing

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over this arrow then if you had a way to

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stitch them together if there was a good

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way to do it what you'd end up with are

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a bunch of random sequence polymers and

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that's that's fine however once you make

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these these random sequence polymers if

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unless you can disassemble these

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polymers you can't you're gonna use up

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most of your monomer material before you

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get to a useful sequence before you get

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to a sequence that's able to say have a

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stabilizing interaction with some other

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molecule so really what you need in in

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the absence of an enzyme or you know a

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biological system is you need a

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reversible chemistry so these these

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monomers if they're all just floating

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around together if they can stitch

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together and form a bunch of different

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sequences but then they can break apart

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and then reef then restage together in a

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different way we can sample many

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different sequences from the same from

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the same pool of monomers we can recycle

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them and so here what I've highlighted

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here is oh look this is the sequence

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that this is that sequence from the last

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slide here and so by random chance you

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may be able to form it and what's nice

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about this is that this idea is that you

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can you can reuse the monomers and this

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this has been a problem in particular

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for peptide chemistry on the prebiotic

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earth but recently in the Center for

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chemical evolution a lot of

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collaborators here have come up with a

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way that we think we can we can get a

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system like this on the prebiotic earth

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okay so you've probably seen this

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picture a hundred million times that's

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Stan Lee Miller's experiment seminal

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experiment where he showed that you can

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create amino acids from simple prebiotic

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we plausible mixtures and so everybody

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knows that and as Erin said earlier and

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as is less popularly known you can make

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amino acids in these mixtures but you

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can also make hydroxy acids so here on

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the left there's an amino acid right and

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it has this an amine function and then

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here is a hydroxyl group for the hydroxy

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and

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so in this presentation they're always

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gonna be blue or red blue amino acid

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red hydroxy acid and so you can make

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both of these in model prebiotic

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experiments and furthermore you can find

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these in meteorites you can find these

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people people have been you know

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analyzing meteoritic samples for many

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many years now and you can find lots of

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amino acids lots of hydroxy acids so we

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know that they were very abundant so

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let's suppose that you only had amino

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acids because historically what

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scientists have done is they said AHA

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we're going to take amino acids and

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we're gonna try to make a peptide out of

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it and that peptide will hopefully have

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some function well the problem with that

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is that if you have a bunch of monomers

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a bunch of amino acid monomers it is

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difficult to get these two to stitch

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together it's difficult to form a

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polymer from these amino acids usually

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it requires some kind of activation

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chemistry in order to get polymers and

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it's difficult to get long polymers and

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it's generally thought that if you want

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a functional sequence it's gonna have to

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be a pretty long polymer think about how

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large a protein is you know thousands of

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amino acids so if it's difficult to you

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know get three amino acids stitched

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together then a thousand is unheard of

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but beyond that there's another problem

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Erin mentioned this as well if you have

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two amino acids stitched together as a

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dimer they will cyclize very easily and

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this actually will will eat up a lot of

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the it will eat up a lot of the products

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that you would wish to go further along

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in the polymerization instead they get

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stuck in this cyclic what's called a die

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keto piperidine trap so a couple years

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ago in the center Center for chemical

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evolution a bunch of collaborators got

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together and said aha what if we mix

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together amino acid and hydroxy amino

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and hydroxy acids together and what if

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we did like a prebiotic earth kind of

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simulation experiment if we had

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evaporative conditions so if if we had

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amino and hydroxy acids in solution

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together and we've heated this up and we

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basically boiled that water off or let

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the water evaporate off that's

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our way of putting it then what will

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happen is when that water evaporates off

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we're gonna drive condensation reactions

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between these and because of an ester

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emmett exchange mechanism that I won't

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really get into here but Aaron Aaron

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mentioned it what you end up forming are

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copolymers of the hydroxy and amino

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acids and that you can get copolymers of

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many different sequences and of many

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different lengths now what's important

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here is that within this polymer you're

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going to have the the peptide bond

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that's that's alright that's an amat

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that's the one that we're used to seeing

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in biology but you're also going to have

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an ester in there and that becomes very

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important because the ester is way

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easier to break using say water by

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adding water to this then an amen' so so

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we thought okay what maybe we can

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explore some of these molecules so what

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we did was we cut down a little bit

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that's a little bit of a sequence space

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of these products so we can form you

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know I only have three things here but

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you can actually make many more

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sequences and many other combinations

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and of end of much greater lengths you

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know up to I think ten or ten or twelve

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amino and hydroxy acids in total and so

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what we do here is we say okay what if

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we started with this with this hydroxy

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and amino acid dimer well if we start

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with that then what you'll notice is on

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the on what would have been the end

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terminus there's a hydroxyl group here

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and on the c-terminus that's the

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carboxyl group right and if we put these

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if we have these molecules okay and

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these are groups these could be any

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sidechain functionality these are you

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know your standard amino acid side

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chains and if we have these in a

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solution and we evaporate the water off

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then the water yet the water is

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evaporating up and we actually drive a

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condensation reaction between these

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monomers and so what you end up with is

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they start stitching together using

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these esters so here I have them kind of

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divided like look we made we put three

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of these together but that's what's

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happening when we drive the water off

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what's cool is that when you add the

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water back is that you can take these

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polymers and

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break them back apart into the monomeric

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units or the starting units the the

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units that we began with and it's kind

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of cool because many of the products of

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these of the reactions that I was

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talking about that the guys in the

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center did a few years ago they're

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they're always a peptide that is camped

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with the hydroxy acid and that allows

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for this chemistry now if I can take

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this monomer form a long polymer and

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then break that polymer apart that

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sounds exactly like what I mentioned in

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the beginning doesn't it we have a bunch

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of monomers and we can form a bunch of

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random sequence polymers here it's it's

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very similar now can we do better than

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that because remember what we want to do

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is we want a very specific sequence so

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like this guy here I had it binding and

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what an RNA helix or something so can we

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can we do better than just random

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assembly and I believe that we can so if

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we allow this these reversible processes

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to occur if we let you know the monomers

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form polymers and then back and forth

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then if we were to add a molecule or add

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something to to our system add something

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to our reaction that might stabilize one

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of these products like this for example

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then what we would expect is that that

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product is more stable and therefore

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when I add the water back into the

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reaction those aren't going to degrade

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so we would expect the abundance of say

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this guy to increase in time while

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everything else kept breaking apart and

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reforming and so that is that's what

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we're investigating here so I've got a

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little bit of change in notation here

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but basically what I want you to see

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here is that these little red and blue

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guy here this is say the starting unit

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and what we can do here is we can have

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these in solution and we can stitch them

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together by by evaporating away the

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water and in the presence of a of a of a

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template molecule like a cation or you

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know some kind of some kind of organic

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molecule for example then what we expect

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is that if something can bind to say

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that cation it will be stabilized or at

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least some of those molecules will be

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stabilized and we will see there

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increase and it will kind of shift the

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equilibrium the thermodynamic

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equilibrium of this system in their

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favor and so that's that's basically

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what we're working on and if you want to

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talk to me more about it later that's

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fine I love talking about this stuff and

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that's really all I've got for you guys

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yeah thank my lab thank the Center for

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chemical evolution any questions

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[Music]

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what about amyloid forming peptides

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they're short and they so select you

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don't need to think about the ligands

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because a lot of metals will facilitate

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hydrolysis also but if instead of

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choosing glycine you take peptides that

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confirm amyloid sequences such as

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Vanille alanine you can have the

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selection of the surfaces of structures

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of sequences that have already useful

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structures yeah just by selecting the

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sequence yeah so actually we're

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considering several things like that so

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if yeah if for example we had phenyl

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alanine here as this moiety then and and

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some charged moiety here at for the for

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the sidechain here what we would expect

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is kind of a Nancy philic kind of layer

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formation yeah we're definitely looking

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into things like that because that would

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be a that'll be a very simple way to