The Physics of Life: How Water Folds Proteins - with Sylvia McLain

[Music] [Applause] I think 50 and they made a very very important of every his name was Harold Tom runs it and I know you're all sitting there thinking I should maybe this is but what he did was in as every comic book reader knew and every tablet reader knew for the mere price of 75 cents or a dollar 25 in my day you can send your pre address stomp stamped envelope off to a clearing house in New York and you get back a bag of sand and in that bag of fans contained instant life sea-monkeys you can still buy see monkeys but see monkeys are actually a real critter they're a crustacean just like a lobster and they go through this amazing lifecycle so what happens to them is even though they live in water they can lay their eggs and those eggs can come to become completely dehydrated and now all you have to do is I've water a thousand years later long enough for them to hang out in the clearing house so Harold's on Brunswick could sell them and you can buy them and they come to life so you can still buy these things there are about two pounds fifty on Amazon so you have to buy about ten of them in order to get your discount for delivery or you can if you're kind of worried about the dubious claims that they're going to build little sand castles and they might do that in your sink you can go slightly more upscale pretend like your naturist and vice try up world which is their seven pounds and you get free delivery on that I think because they're trying to push it so I did this i bought some triops and i tried to time stamp the day that i did it with some news but unfortunately the news is going back and forth on this issue a lot so it doesn't really work but anyway here's my tryouts in my dark kitchen and oxford and i agree some sea monkeys and this is what they look like about five months later now amazingly they swim around now the kenai among you will realize that this is a different container and it's because I ripped this off of YouTube because mine are dyed okay and this is why I'm a physical scientist and not a naturalist okay but the interesting thing about this is you just add water and you get life okay now you can't just add any old liquid so if you think about some other liquids in your life octane is a good one so Octane's what you run your car on and if you're like me and you really like past 1960s cars before they run we knew they weren't environmentally friendly you want to run your your car on high octane it's part of my birthright I'm supposed to like it okay but if you put sea monkeys in octane they will not live okay they will die and I didn't do that in the interest of not harming any sea monkeys in the making of this lecture okay but this is what they look like so if you look at these two liquids this is what they look like this is hexane and this is water okay and what do they look like clear liquids really exciting they kind of moves the same right they're based in the same container this one looks a little bit different if I shake it up I get bubbles they look the same so why can I not do this well it turns out now this is hexane this is not octane because I don't have any octane this was in my lab and so I took the convenient thing in my lab but hexane is actually quite similar salty but it turns out and really in order to really understand how this works you actually have to look at water on the microscopic level you can't just look at these bulk properties of a liquid and decide what it's going to do so there's a difference between these two and I'm going to draw for you and hopefully this works and this is what the molecular structure of water looks like okay it's just that oxygen atom attached to two hydrogen atoms and I'm sure you guys have seen this before maybe sometimes it's on the back of football jerseys these days because chemistry is cool and this is what hexane looks like it's just a bunch of ch2 atoms connected together it's a bit dull compared to water okay but these rows have hydrogen so the kenai among you will notice that one has an oxygen one doesn't that's the answer you must say okay water has oxygen well thing about and you would be right in part okay because the thing about oxygen is also all atoms have a positively charged Center with electrons that rotate around them okay and oxygen really really has a high propensity to pull negative things towards it bit like my grandmother all negativity poised towards the oxygen okay and it's a big oxygen home okay where is it hexane and carbon carbon is perfectly happy to share and so you actually end up with an even charge distribution across this molecule which does not exist in water so this is slightly negative charge we do this little cool Delta because we're scientists but this shows that it's a slight charge or not a full charge okay then we have slightly positive charge here and that's a tiny little bit of difference so now some of you that have had a little bit of chemistry will be thinking yeah but come on water is not the only liquid with oxygen and you'd be right ethanol everybody's favorite liquid right everybody's favorite liquid next to water and this is ethanol and you can see the ethanol and water and exhale and water they look exactly the same right now if you put this sea-monkeys in ethanol you don't just get drunk sea monkeys okay they don't live okay and then we have special molecules in our body that I'm going to talk more about that allow you to metabolize ethanol but you can't you also should never drink pure ethanol okay so this is what ethanol looks like this is a molecular structure retinol and it also has an oxygen in it so what are we going to do now and it also oxygens again oxygen has a high propensity to attract negative things towards it and so it still has a slight negative charge and the hydrogen still has a slight positive charge but the difference is the direction okay and this is a tiny little difference this is one of these little differences that you think yeah it doesn't really matter but it matters very very very much because in this you get life and in that you don't there's a huge difference okay but water in itself is not sentient okay and you all know this because you don't have to worry that when you leave your tap on that it seems as a loss over it is and when you leave your tap on that water is going to you know make some sort of invited friends over you might worry about this Israel homeopathy but waters not going to fight friends either had played poker games in your kitchen water and has not created the work of stroke Shakespeare it's just not going to happen there's a lot of other molecules that have to do this and what's everybody's favorite biological molecule what molecule do we always love to talk about with life DNA well you know DNA is like the middle-management of molecules all it does is give something else to the plan right so all it does is tell your body how to make proteins proteins do everything so you're breathing right now I hope I hope you haven't passed out yet right and when you breathe you have little proteins that carry the oxygen to all the muscles in your body okay I'm walking around right now because and I'm using my muscles to do that and perhaps you're twitching to try to keep yourself awake right and you're using muscles to do that and all that work happens with proteins and DNA tells you how to make prisons and that's it so it's off at the bar having a metaphorical drink while proteins are doing all the work proteins are also the most diverse thing diverse biological molecule we have right so they estimate now nobody really knows what this is but they estimate there's about 80 million proteins in the world that's a lot of stuff but they were made from a surprisingly small number of molecules and here they all are so all of the proteins that you have in your body your bones your lungs your your muscles your hemoglobin that carries oxygen to you right it's all made from these 20 molecules okay and that's it which is kind of sad isn't it okay but how do we get this huge diversity of life from this tiny number of different molecules how do we actually get that so if we look here right you they all have the same functional group on them you can see them all here everybody's got one right so this is actually how your body joins these molecules together so they're irrelevant all it makes the difference here is these little bits on the end so these are all different molecular structures that make a difference okay now you all have a pipe cleaner and you're probably wondering why you have a pipe cleaner so what I want you to do while I'm talking well of course putting most of your attention to me is sort of pet play with your pipe cleaner and start folding them into something okay I don't look at your neighbors and my group don't cheat okay so don't look at your neighbors right just kind of view it here on the sly and we'll come back to it later and you don't have to if you don't want to you can just be left out okay so all of these things have to link together to make a pro a protein okay and the way that this is what this these are amino acids here and they all linked together through these chemical groups to make something that looks like this okay and all they are is long chains of amino acids one after the other after the other after the other after the other into these long polymer chains okay now we immediate and there's only twenty of these things so how on earth do we get this amazing diversity of life from just twenty things so most proteins are somewhere between a hundred of these long to fifty thousand of these things long even a hundred thousand okay there's a huge number of different sized proteins and different shaped proteins with different links proteins so if we just imagine minute one of our smaller proteins which is only a hundred amino acid long spree tiny okay and we think about how we can combine that so we have a 100 amino acid protein you have 20 options at each position one position doesn't presuppose another position it's completely random you end up with that number of different options okay and that number turns out to be does anybody know off the top of your head many many zeros that is ten do ODIs iliyan I didn't know that number until this week two I didn't know a number that big existed okay but that is Ken Dewar to cilium a whole lot of diversity so if you all stop for a minute and look at your pricing or sorry and look at your thing does anybody have ones that without cheating that look the same as their neighbors so you know what this is why we need DNA and I reluctantly say this is why we need DNA because we don't end up with this okay we end up with something that's directed we end up with something that gives us the right structure in that felt that's all D and I really does for us okay occasionally it makes a virus occasionally it cures cancer and yeah whatever okay so this is what proteins really look like we're not just big long sliff like creatures with long polymer chains of proteins they actually have to fold up into structures to be something so this one here is hemoglobin okay so this is how you're breathing right now and it's happening really fast okay if you get too much acid in your blood so if you ever Sprint's too fast like for the train your muscles will hurt because you build up something called lactic acid you have a protein to sort that out for you okay this is a muscle fiber and if you want to be really super cool you can actually make videos of these and all that happens when you contract your muscles is that you have proteins doing this okay so that's a little pulley protein it's called actin and it's going to say motor protein here in a minute for me thank you and this can walk along your muscle fibers okay and proteins you see any DNA I don't see any DNA proteins are doing all the work yeah and all this work has to take place in solution okay so we have proteins and we have water and we know that somehow so I just told you that DNA helps us make these long chains of molecules right and here he is here right but it doesn't just have a long chain it has to fold up into this structure and this is the miracle this is a really interesting part right you can take this protein and you can put this protein into solution and every time it will form that structure over and over and over and over again and I don't mean sort of like that structure like your lovely pipe cleaners I mean that structure exactly if it didn't we wouldn't be here we wouldn't be like okay and that's amazing that's absolutely amazing that you have all these amino acids and just water encode to do that and there's another famous man in the 1950s maybe not quite so famous as harold von broom hood right and his name is Anton Singh and what he did was this exactly he took egg white lysosome so it's just it's just the protein in the head an egg a hen egg right which we eat all the time and he took that protein and he put it in water and he looked at the structure of it and then he put it in a chemical called urea that unfolds it and then he took it out it refilled it and he put it refold it and he did this and he did this it must have been great being one of his graduate students right the separate you did for months and months when people have repeated it so he's not the only person that's ever done this so you can fold an unfolding can do that all day long and it works and the only thing that you have to do is have the right amino acid sequence and have water just instant life just add water now if it doesn't work we the reason why we study this is because it's cool it is really cool right nobody knows how this works but the other reason is if this is linked to lots and lots of diseases so Alzheimer's leaks proteins not folding properly so in Alzheimer's what happens is the proteins unfold and then they start platting together sickle cell anemia okay sickle cell anemia is a disease of hemoglobin one amino acid changes and the whole thing falls apart one amino acid the whole thing falls apart so these tiny little changes in electronics and molecular structures make the world of difference to whether or not your life okay so we have of course a theory about this because we're scientists and we like to have theories about things and the theory goes is followed at something called the hydrophobic effect all right and now I'm going to do my one demonstration which hopefully so I have been supported by Amazon but after by all of the grocery store chains around Britain so I some Sainsbury salt that's easy to buy and I bought the cheap corn and olive oil okay so some of you cook I know and when you put olive oil and salt what's going to happen somebody want to guess what's going to happen so just sits there on the bottom it's really quite boring right so oil is hydrophobic okay well and you know this you know you walk around when it's in puddles in London and you see this oil sheen on the surface of those puddles that's because the oil is hydrophobic and it flakes on top so if you put this in here so the theory goes salt is hydrophilic so salt loves water oil hates water so what happens is this can't dissolve so you have this thing that's hydrophilic that can't dissolve in something hydrophobic and then all you've got to do is add water this very information the theory on this is very long technical papers it's not just this experiment so if you take this and you swirl it around what you notice is that the salts starting to dissolve okay but the salts not dissolving in the oil of the salts dissolving in the water because it's hydrophilic and I might have to use something to stir this up but we'll come back to this in a minute since it's a slow process okay and that's all it is so the theory goes that you have this hydrophobic stuff and it's afraid of water so water actually inspires it somehow to fold into the inside okay so all the hydrophobic parts of the protein because some of those amino acids are hydrophobic some of them are hydrophilic they actually fold in together and make your protein and voila magic you have a protein and hopefully that will actually dissolve but I was told by the nice people that helped me arrange this that if my experiment didn't work I can just say well this is real science okay so here it is hydrophobic effect theory so there any evidence for this okay so the theory gets a little bit more complex than just oil and water and what we know from this theory so we know from the second law of thermodynamics which is the best scientific law we have that any spontaneous change must increase the entropy of the universe this is a law okay proteins fold spontaneously therefore the entropy of the universe must in now this mystery okay and so the folding of proteins has been linked to a favorable and tropic process but what the theory tries to do so this is a microscopic observation so it's just like me looking at these big flasks full of a liquid okay entropy measures our big ensemble which is this liquid it doesn't look at things on the microscopic level all right and so the theory goes as follows the theory goes is that I have this peptide here he is and water around these hydrophobic parts orders itself so in liquid water waters perfectly happy to dissolve the hydrophilic VIX which of the oxygen and hydrogen and nitrogen containing bits but around these big chunky carbon bits so with these lines at the apex of all these lines as a carbon okay so that's what those would like and that water is structurally or ordered around there water is not happy like that okay and I'm sorry I said happy I always get mad at my students when they say water is happy because I always say that water actually doesn't have any emotions and so don't say that now Here I am saying it but we're at a public lecture so it's okay right so water is structurally organized this lowers the entropy of water and then water doesn't like that so water goes flying off into the atmosphere back with what other water molecules were it's entropically more favorable and that's where the magic happens now is this a good theory well it's a theory that is nice to explain I'm hoping that you all understood it but there's no evidence that provoked the series all not one shred okay so all we know is spontaneous protein spontaneously fold in solution and that must create an increase the entropy of the universe but we have no scientific evidence of this water structuring problem nobody has ever seen that it's all been done by a computer model and there's nothing wrong with the computer models right and this is a nice thing about scientific theories is they work until they don't okay and when you have new pieces of evidence or if you're a physicist a new observable right then you have to change your theory you have to adapt and that's one of the things that we're trying to look at is how water what does water do how does water actually interacts with proteins in order to help them fold diffraction so this is this this is a animation to try to lull you into submission right it's trying to hypnotize you so now you're going to believe everything that I say so I'm telling you this other theory might be wrong and now you can just stare at this and then we'll just I can go off down to the club and you can just continue to stare but what we use is something called diffraction and there's a lot of wonderful our eye talks like this one that are on the web that talk about diffraction I think Jim al-khalili someone so if you're really interested in diffraction you can go watch one of those but I'm just going to go through it quite briefly so what you can see is there's two sort of slits here right this is just a double slit experiment okay but you can imagine those slits not being flipped but rather being atoms so I have an atom here and I have an atom here okay and what happens is I have this wave of something coming towards me but because it's sort of a particle and sort of wave the particle can hit me and then it spreads off as a wave and what I get from this is I have a distance between these and I get this characteristic wave pattern between the two yeah so what you do is you have a probe coming in bounces off the two atoms they both have two waves and you can look at that characteristic wave pattern and that can tell you where the positions of the atoms are so it's a bit like being at a ponds a nice Mill Pond and putting it throwing in a pebble and what happens when you throw in a pebble you get ripples right and what happens when you throw in two pebbles simultaneously you get ripples and they either constructively or destructively interfere if you want to use techie scientists to talk or you can see that the waves either get bigger or they cancel each other out and that's all we're measuring is those characteristic wave pattern so now most people's favorite diffraction probe is a X for everybody loves x rays like VNA x rays in DNA our favorite molecules and favorite probes but x rays are really lousy to measure water okay so they're really bad at that because if you look this is a relative intensity of scattering so x-ray scatter off electrons so all atoms have a nuclei which is positively charged which is relatively small they're all orbited by Tong's which makes a relatively large cloud okay and x-rays scatter off of those now if your uranium atom that's for the goods because you're really visible if you're a hydrogen atom that's really bad because it's small and it's hard to see okay so what do we use we use something called neutron diffraction so this the one the picture on the on your left is I think yeah your left is an x-ray image of a cigarette lighter so it's just like when you go to the doctor if you break your arm and you get an x-ray when you put your arm on that imager what you see is the bone and not the fight okay but hits so here you can see the metal and not the beat a but the one on the right is a neutron image of a cigarette lighter and what you can see is the butane which has a whole lot of hydrogen in it and that's what you can see so that's why we use neutrons now I'm going to hurt you have to get me chance from somewhere you can either get them from a nuclear reactor or you can get them from one of the best sources in the world so you don't have to go to Paris you don't have to go to Milan you can go to Didcot and did taht actually is the home of one of the best Neutron sources in the world arguably the best of course I think it's the best because I use it and what it does is it creates neutrons through a particle accelerator and here's another plug if you want to learn about particle accelerators Susie she he does a really nice series for this institution on that but this is basically how it works this is just a brief overview of how it works so basically if you look at the red thing there that's your particle accelerator so you have a hydronium ion source and all that is is a hydrogen has a proton and two electrons all right and it's producing those as we run down the red bit so here it comes there it goes and so then they start going faster and faster and faster and you can control them with magnets okay it's got a charge you can control it with the magnet then it goes into the synchotron bit which is this bit this swirly yellow bit and they start going about 97% the speed of life and they go so fast that you can actually pull the electrons off them and you're left with a naked proton okay then you take that naked proton and you on the circle again and you bum bar to talk targets you're basically throwing it as hard as you can at a big Neutron target and in this case that I think it's tungsten so it's tungsten metal it could be uranium you've all heard uranium and what happens is you have all these neutrons that go flying off in every direction now neutrons are neutral that's why they're called neutrons right and they're very hard to control so we have to be first to slow them down mix they come off really fast then you slow them down you slow them down so you can get your matter of and you do that by running them through a very very thick chemical where they have lots of collisions and they slow down an energy so it's a bit like trying to herd caps right so protons are pretty you know compliant and they do what the magnet tells them but these things come off on all in all different directions but the nice thing is you can reflect them so I think I'm bouncing down the collimator and then they finally get to your sample and then we can finally do some diffraction which is great and those are created by Isis so here we go back to reservation to fractions we love the fraction the fraction all you're measuring is the wave pattern when you scatter off those two atoms that's it but we're doing that with neutrons okay so this is what they look like we don't just measure the wave we measure this wave pattern you can tell this sort of looks like the cross-section of some of these waves I hope so in this example you're looking at the distance between two blue atoms and this is real measured data for a different sample but that's the distance between those atoms now if you have blue atoms and red atoms you're going to have blue blue interactions blue red interactions and red red interactions and then you can sum all those together and get the plot on the bottom okay and that's exactly what we measure but you can see instantly we have a problem that's what we really have and I'm also very pleased by this picture because I finally found a use for damien hirst and here's all the different atoms that we have okay and we have to measure that and that and all the distances within here all at the same time so all of our diffraction patterns Kerry Kerry all this informations we're going to do what we're going to do is we're going to do something that's really cool it's called niche on the fraction with isotopic substitution which is long word for just saying the deuterium and hydrogen scatter different so differently because I'm not still in Tennessee right so you have hydrogen nucleus hydrogen nucleus has one proton and one electron a deuterium nice trous nucleus has a neutron a proton and an electron okay and interestingly they have different scattering cousins so I can turn that into that so I can label everything so that I can see different bits in my samples and to explain this to you I'd like you to all stand up it's a good time to stand up okay so if I walk in this room and I look around at you there is no way I'm going to remember where you're all sitting right because there's like to my face and B because you're all different but if I can have you sit down I can measure a pattern so you see I can measure a pattern with just you standing and just you standing so I know you're there and I know you're there and you've gone away now if I can have you sit down I can measure another diffraction pattern that just has you standing up and you're gone and you're gone and if you want to sit down then I can measure this as well so I have no information right so if I can just have all of you stand up again then I can use an x-ray begrudgingly okay you are all deuterium and I'm going to show you what that looks like just right now and you can sit right down against Felix so that's what it looks like okay so what you can so the cool thing about this if I can pick any sample I want to and you know that I'm going to get to measuring some kind of probably promise I'll get there measuring some sort of protein in water and you can see that I have all these different isotopic substitution things and this is all the same sample okay it's the same sample with different deuterium and hydrogen level labels and I hope you can tell that that's different okay so they all look slightly different you guys are the second one down from the top and once you start standing and sitting and standing and sitting I can mute different parts of you out and that allows me to combine my patterns in order to figure out where each atom is okay and now I have another problem so now I have another problem so this is nice right does anybody know about crystallography yeah some of you know about crystallography great guess what that's not a crystal we don't have a crystal we're in a liquid we don't care about a crystal and a crystal it's like four degrees Kelvin if you want to look at a protein where water is not moving right we want to see the water and we want to see proteins as they fold more after they folded in reality this is what we have we have our molecules moving around and we're getting characteristic wave patterns off of them and they're moving and we put the terraeum on them and that's fine but maybe it goes away and it comes back and goes away so we have a really complicated problem it's just a lot of atoms moving around but we still measure characteristic wave patterns so that we get the average picture what's going on which is cool right so this is real data it wasn't thrown by damien hirst or any of my graduate students it was actually measured I've just put it in nice colors because it's easier to see now the other problem we had it's not quite that simple because we do what every scientist does now that nowadays and that is we use a computer simulation because we have so many different interactions between all our molecules in here we have to simulate them in this computer but this is pretty easy right what we do is we get a box of molecules on your computer it's kind of like playing a video game at least this is what I try to convince my students I don't think they believe me yet but you take the molecules that you've just measured you know what you've measured you hope right because you can measure it you can weigh out a bit of peptide you can lay out a bit of water and then you can actually put it in your Neutron beam and you can measure a pattern from it and you know what it is and so you build a box of molecules on your computer and then you move around those molecules until you actually get them in the right structure that compares with your data so it's called fitting your data so we actually this is one thing that we do that's really unique and most people that use computers don't do this is that we actually take our data and use that as a constraint for our computer model and that's really cool because we know at the end we're going to have a model that's consistent with our measured data right so finally some of the stuff that we measure so this is again real data and if you can see there's a black line which you can't see very well in this graph and there's all these colored dots and all those colored dots are measured data the black line is our computer simulation of that data okay now what we want to do and the line in the middle is the difference between the two so we measured this little tiny peptide to help solve our problem and the reason why we measured this peptide is because it's known to occur in a lot of proteins that's fold so proteins fold and they have to turn around over on themselves as you know from from your lovely playing with your pipe cleaners is that you actually have to form some sort of turn to form a complex structure and that's why we picked it and we have this nitrogen 1960s picture of it so you have to turn them up but what we actually measure in solution I just said they were removing so if you all can hold up your thing so hold both ends of them you can keep them folded some of you have a big blob so maybe that won't work so well but just pretend like you're holding a tin right so what I'm actually measuring in solution is a snapshot of you all all at the same time right so I'm measuring all of this all at the same time I'm measuring I'm open I'm measuring them close and I'm actually adding those together right because I want to look at the peptide when it's completely open I want to look like look at it when it's 1/2 squared and then I want to look at it when it's close because I want to know what water is doing at each of those steps okay all right so this is what we get out of our computer models so what you can see is this is a small peptide it's just a simple peptide and it occurs in turns and proteins so proteins have to turn back upon themselves and what we do in our computer simulation is we measure this average structure so we measure all the water and where it's most likely to go we measure this for a variety of these molecules so the first thing we learned about this molecules is indeed folding so we went from this which is wide open to that which is folded okay so I've gone from this to this and a measuring basin solution and what this picture is is this is a three-dimensional representation of where the water goes so that red so oxygen atoms are always red nitrogen atoms are always blue I have no idea why hydrogen atoms are always white then so this is the hydration around one of the oxygen atoms and it looks like a halo it's really nice halos and I hope you often see that it looks like a halo and what so what you can see though is that water is actually bonding to those remember let remember that water oxygen is really negative so it really likes negativity so what it's actually doing is drawing the waters to it and it's put them on the sides of it because they didn't start to repel each other and that's really smart but then we see this we see something completely different we've seen hydrogen exactly on top of this oxygen atom it's just sitting on top there and that's weird that's not where it's supposed to be so you're just going to have to trust me this is what scientists do isn't it like trust me I'm a scientist right is that this is more normal okay this is a more normal thing we usually see this hydration that's around the outside and on the top we see something different so just to prove to you I know this is really scary slider I know but the reason why I'm showing this slide is because I don't want you to think that I just drew this on the back of an envelope on the way up here okay so you can draw these pretty pictures but these pictures a lot of mass goes into behind this picture and I have a lot of really clever people that work for me that help me learn how to that we've learned how to do this so basically all this flow chart shows is how we actually pick out where what water is doing so we can figure out where water is and we can figure out where these patches of density are around our pet side that's really exciting but what this graph shows you is that we can actually look at those patches of density here and here in here and here and then we can map out the different angles to figure out exactly where a water model molecule might go so we know remember at the very beginning I told you that we have this orientation of water and it's only slightly different from what you have an ethanol and that makes all the difference in the world okay and here it is making all the difference in the world because there's only certain ways that that water can orient itself okay and that's really kind of cool and we can actually map that out so we take our neutron diffraction data we take a box of molecules we fit it to that data we pull out the average hydration and then we look at exactly what these water molecules are doing and what they're doing during each folding stage of the peptide and then we end up with pictures like this so all that work boils down for that okay but what you can see here is this is an oxygen atom and this is the nitrogen hydrogen atom as the water is oriented perfectly to pull those ends together so what we think water is doing is it's acting like a glue so water's sticking itself to that oxygen sticking itself to that nitrogen starting to get that proteins fold together now of course we're scientists so the first thing we do is think okay that's probably wrong so let's go test and make sure we try to disprove our theory this is what you should do if you're a good scientist sometimes that's not really that's kind of painful to do right you published a paper you're all excited you have any theory and then you go and test it and you're wrong but it's part of the way we progress so we're sort of two steps forward fifteen steps back and scientists are people so we did get stuck in our ways so we measured this longer peptide and one of my really excellent graduate students she figured out how we could go through the simulation and actually categorize open versus medium versus closed okay and she spent a lot of time doing this so it looks really good but I hope you can see that you go from open to medium to close open medium closed and then what she did was shoot these little hydrates she picked up the hydration patterns around different sites in the molecule and this was the one that was different okay and it's right where we want it to be right as you can see this is a nice halo II like structure so water is in a halo like it's supposed to be and then as we close the peptide the water gets clearly more oriented and localized in a certain place all open and happy as the peptide folds it moves aside then we can also pull out this picture where we can find a sequence of events so we start here with folding we have a water here the water reorients itself and then we have closing so we have water pulling orienting closing pulling or in Seng closing do you really want me to say that again right so I can keep saying that but that's really neat and it's only because of that tiny electrical charge in water that that can happen right so then we measure that and we have two examples now right but two examples don't make the end of the story so then we measured something else we measured this really simple structure on the bottom and again this is all done with neutron diffraction we also do other measurements as well we do some NMR measurements and we different different kinds of simulations and we spend a lot of time trying to prove ourselves wrong I mean probably tediously so but that's what our job is and so what we notice from this is this is a completely different molecule okay this is this is a hydrophobic molecule so remember before oh and so remember before we've looked at high-end Latour the salts gone alright so all the salts Mesa guy okay don't look at the bottom right so all the salts mostly gone because it's the hydrophobic bits in the hydrophilic bit so we thought well you know we're going to do we're actually going to take a hydrophobic thing and we're going to stick it in water and see what happens but we couldn't just stick it in water we had to stick it in water and methanol mixture and the reason why we had to do that is because it had to have a little hydrophobic surface or it won't go in a bit like the oil so what we thought was well okay we've got this methanol molecule here so this is the hydrophobic bit and this is a hydrophilic bit and this whole thing is meant to be hydrophobic and we thought well all of these mess all the hydrophobic things will stick together just like this all the hydrophobic things in here are sticking together but on a microscopic level that is not true so what you can see is these this is methanol so that H bond is oriented right towards that hydrophobic thing and now the water is oriented right towards that hydrophobic thing that's wrong it shouldn't be like that we were went and we want to know why okay but the interesting thing about that is it only happens in at all so we've measured what we don't just measure pet size these are drugs and I should probably give somebody a prize if they knew what drugs these are so this is cocaine so cocaine can easily cross into your brain this is why people use cocaine this is why cocaine is a very effective drug not just recreationally people use it for medical purposes because one of the interesting properties about it is it has to be most drugs have to be both hydrophobic and hydrophilic in order to work okay especially drugs that cross into your brain so they have to go to your bloodstream but they still have to be hydrophobic enough to get into your brain and nobody really knows why so we've measured a bunch of these as well and we see the same sort of theme okay these are all water molecules they're different colors so you have different students you have different color signatures and I know who they are but what happens is that we can see that water is actually mediating all of these structures so the way the molecular structure seems to be happening or is controlled by water and it's controlled specifically by an orientation of water and we can only see this because we look at things on the microscopic level and we're very very very very very careful measurement okay so are we right this is the hardest part about being a scientist so we're looking at stuff that's right on the edge of what you can see so all of this structure that we do right so what we what we do is we take all these measurements and microscopic structures it's been lots of times seeing all these things we try to look at water we try to look at how things stick together and are we correct or is this theory of hydrophobicity or correct where water is just really kind of uptight and disordered and doesn't move anywhere which one's correct well we don't know so the beauty about biochemistry is the following so I'm a physical scientist and I work in a biochemistry Department is that biochemistry has no periodic table it doesn't right chemistry has a periodic table there are rules there are things that your elements must do if you put things together you know how many protons you have you know how many electrons you have but biochemistry doesn't have that so one of the really difficult things about this hydrophobic effect theory it's because it's very hard to energetically deal with and what I mean by that is the following is that your unfolded protein and your folded protein have a very tiny energy difference so normally what happens in a chemical reaction and the flask is you put two things together and the thing with the lowest energy will form right and it will form spontaneously and it will be pretty obvious but that doesn't happen in biochemistry that doesn't happen in your body your body is a carefully controlled organism so if you have if your blood your blood pH has to be about 7.4 that's it that's a really go to 7.2 and it can go down to 7.6 but it needs to maintain about 7.4 and the reason why it needs to do that is so that you can live and your body can do that if you get in your proteins if they aren't if they're at 7.6 they unfold if they're at 7 fan-fold they have to stay exactly at the right pH so in the energy landscape to use a technical term it's very tiny okay you don't have these big energetic changes and reactions like you do in chemistry so what do you do about that I don't know so it's still in its discovery phase right so we're actually creating the periodic table of biochemistry that's what we're doing at least that's what we say that we're doing okay so the thing that you need to ask yourself when you read sites so the thing about salt at this so the thing about water and the way water Orient's is water is the only molecule that can do this so there's been a lot of studies where people try to find water on the planet it's never been think they found it yet because the only thing the way this happens is with the life on Earth as well okay so it's something to actually think about why we work now the diseases related to protein folding are still not cured okay most of the way that drugs works don't most of the way the drugs interact with your bodies are still unknown okay I don't know if you know this but most drugs that you take people don't know how they works okay especially drugs that cross into your brain which is one of the reasons why we're studying there actually don't know the mechanisms of how these things work there's not a lot of information about that it's quite old it's all sort of empirical so part of the research we're doing is to try to uncover these mysteries and try to figure out why water is the elixir of life and I'm actually done a little bit early I think so I think I can take some time for some questions [Applause] you

Channel: The Royal Institution

Views: 117,937

Rating: 4.8099041 out of 5

Keywords: Ri, Royal Institution, physics, chemistry, science, proteins, protein folding, water, h2o, life, biochemistry, lecture, talk, sylvia mclain

Id: SaSntOkK-Vk

Length: 45min 7sec (2707 seconds)

Published: Wed Aug 30 2017