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Lecture 11. Proteins and Amino Acid Conformations, Part 2.


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Title Lecture 11. Proteins and Amino Acid Conformations, Part 2.
Alternative Title Lec 11. Introduction to Chemical Biology -- Proteins and Amino Acid Conformations -- Part 2
Title of Series Chemistry 128: Introduction to Chemical Biology
Part Number 11
Number of Parts 18
Author Weiss, Gregory Alan
License CC Attribution - ShareAlike 3.0 Unported:
You are free to use, adapt and copy, distribute and transmit the work or content in adapted or unchanged form for any legal and non-commercial purpose as long as the work is attributed to the author in the manner specified by the author or licensor and the work or content is shared also in adapted form only under the conditions of this license.
DOI 10.5446/18870
Publisher University of California Irvine (UCI)
Release Date 2013
Language English

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Subject Area Chemistry
Abstract UCI Chem 128 Introduction to Chemical Biology (Winter 2013) Instructor: Gregory Weiss, Ph.D. Description: Introduction to the basic principles of chemical biology: structures and reactivity; chemical mechanisms of enzyme catalysis; chemistry of signaling, biosynthesis, and metabolic pathways. Index of Topics: 0:28:13 Amino Acids and Proteins 0:30:53 a-Helices Form a Dipole 0:31:09 B-Sheets Come in Two Flavors 0:34:39 Secondary Structure - Backbone, Conformations 0:44:40 Conformational Analysis for the Cognoscente (White Board) 0:58:07 Amino Acids Examples (White Board) 1:05:01 Conformations to Watch For 1:09:38 Allylic Strain Dominates the Protein Backbone 1:13:10 Disulfide Bonds in Proteins 1:15:34 Protein Structure 1:17:50 All a-Helical Proteins
there were going to pick up where we left off last time last time we're talking about protein structure and I we're going to start from 1st principles today looking at the most basic elements of protein structure and kind of building from there as we get increasingly more complicated OK I so quick announcements as you know so
I mean the reach of the 5 of us get a head start reading chapters 6 will be working on that chapter next week and there will be a mid-term which is 2 2 weeks from the past Tuesday's about a week and a half from now there will be a mid-term of the 2nd midterms and on that will cover through the end of Chapter 6 OK and all mainly focus on all the more recent material since the last midterm and I believe that's like chapter 3 3 2 armed Chapter 6 so sort of the last half of Chapter 3 colossal quarter 3rd of Chapter 3 and then on through the end of Chapter 6 OK that's what the midterm will cover on let's see today is the day that we have assignments that are due and so on don't forget to turn in at the end of the class today just leave them over here again into the TAC arm if you forget dropping by my office because of questions over were going that sort of thing OK let's take a quick look than that of the office hours I have office hours today immediately after classes I and Miriam has opposite tomorrow and next week were back on Tuesday etc. But I expect my office our next week the floating office hours will take place probably
215 to at 315 let me just make that change just so that you know of a case that's also going to be the next week office hours well
armed With seeing this would be a good officer come by to talk about your proposal recall that the the abstract your proposal is due next on Thursday a week from today right OK so weak from today you're going to hand in something that's 5 pages that's 5 sentences "quotation mark I stopped by the just-in-time case let's talk very briefly about the format for those 5 sentences OK this is what I would like to see in your proposal abstracts in OK so the
proposal abstract please tell me about 2 things :colon so let's say I guess so those 2 things are your idea and to how it fits the definition of chemical biology I would say but if the submitting a proposal to the National Science Foundation and how it fits the definition a chemical biology not so important but for 128 it's really important activities I know everyone in this classroom is a creative individual who was lots of great ideas but the vast majority of those ideas are in the area of chemical biology so I'm interested in your chemical biology ideas a case so far and here's what I would like to see in your proposal abstract got it must cover these 2 topics and on specifically from Letisha format not is this color showing up OK will argot sendoff protect OK so abstract art at the start of all scientific communications the abstract is also known as the executive summary in business communications and it's a very very short distillation of the key ideas in a paper and so the goal of the abstract is up to 1 provide those ideas and secondarily to help the reader a good abstract should convince the reader that they want to read the rest of the paper and a great example assist pub that right when you do searches on pub bed it turned you get idea you get these are abstracts edited out and on and I don't know about you but if the abstract doesn't look very interesting and abstract isn't covering the ideas interested and I don't bother reading the paper I'm sure you're doing this as well right if you're not the end of boy you're reading a lot of players abstracts are absolutely crucial to communicating effectively with audiences and again in the business community is called an executive summary and again it's absolutely essential so I'm for anything you're going to be writing after you graduated there's a good chance that you're going to need an abstract the abstract in this class should I'm consists of the following sentences of a so a publicist abstract format and in general I'm expecting something that's 5 sentences if it happens to be more than 5 that's fine if it happens to be a little less than 5 like forward that's probably OK as well but don't plan for something that's like 10 pages of gun in the whole proposal the goal here is that I can provide you a little bit of feedback OK so the 4 in I'm going to just number these necessary number of that numbered people call this number sentence they numbered sentence again and again you don't number your sentences but I'm not going to just give you what I expect each sentence look like a cases sentence number 1 is kind of speaks the problem case of diabetes affects 2 million human about 2 million Americans per year sometimes with grave consequences of pay that's that understates the problem at the big picture of the problem by the way I just made up that statistic about diabetes I don't know what the real number is Kunduz making them just to give you an example OK so 1st sentence on states with big picture of me and I really mean big picture of the problem big-picture problem pesos and start off there this really should be something larger if you're thinking about but I don't know so a better cosmetic or something you know a better entire wrinkle cream that might be nice on but honestly it's not going to fly really is a proposal like if you want come of the better anti-wrinkle cream see and we can talk about how to like hook up with a venture capitalist union money for that kind of thing separately you won't submit proposals to the National Science Foundation because then I can affirm that kind of stuff what I'm looking for is some looking for things that will either increase our understanding of the world around us or solve some problems afflicting the human condition on this planet and when I say that and mean that probably a case so for example if you wanna solve all of you some disease it only affects mountain gorillas and back the important right because we humans have a stake in its during the biodiversity reply planet so that's a big problem I'd like to hear about that as well OK so I'm not going to confine it just to human disease after all I say you know Chemical Biology broadly but at the top at the outset in that 1st sentence you have to show me what the big-picture problem is that you're going to be targeting with your idea and notice that you don't lead off with the idea you actually starting by kind of setting up the a story of in back you should be thinking about this along the lines of storytelling good proposals are kind of like selling a story and so on the 1st sentences instead of sending them this scene setting the dramatic mood and telling us why it is that we should be following along with the next part of case that sentence 1 year and most of them here you have the same impact yet you can do both get so often times and I forget you're reading Iridium's questionnaires whatever I want to cite those stats that appeared in the 1st sentence later in the paper and that would be perfectly acceptable oftentimes there's some overlap between abstract and the rest of the paper and that's normal rate because remember that obstructs the distillation of what's in the paper said some overlap isn't even expected OK 2nd sentence is on kind of focuses focuses reader on your aspect of the problem but say on specific aspects of problem because of the 1st set and cut against you in the door right that 1st sentence is the 1 that says the others as you'd probably out there the barbarians at the gates 2nd sentence says and here's what we're going to do to counter the barbarians the suspected that I know about I'm going to reinforce obviously you would be writing about barbarians but that's a proposal I can think of a moment I'm OK so focused the reader on a specific aspect of the problem 1st sentence was the thing about diabetes and as you know afflicting millions of people 2nd sentence says and there is a target for diabetes a relatively unexplored target for diabetes and called on Idaho Hawke's Bay offers new opportunities for controlling this terrible disease yeah I'm making this up as I go and so on now I know that the the next part of this is going to be on something about hawks said an I'm be looking up rocks 3rd sentence 3rd sentence now focuses on your specific idea of so 3rd sentences we're going to come in and say while some states idea as hypothesis it's OK now I'm not going to ask you to write a sentence that says my hypothesis is X and then I will test this by doing why but you should have something that's a hypothesis do you all know what a hypothesis do we need to talk about hypothesis if this word hypothesis is unfamiliar to you you must look it up you must become familiar with them you I will be looking for a hypothesis your ideas have to be hypothesis-driven OK now I will tell you I'm not really baring my soul and 90 per cent of the stuff that I think about it and I want to work on it is not hypothesis-driven I like the
kind of science where you go out and you explore something that you don't know what you're going to get a look at I like fishing and I love throwing a line in the water and not knowing what kind of beautiful fish is going get snagged by that 1 that actually fascinates me I will do that time and again for don't hours per day in miserable conditions because I just love the thrill of the venture of not knowing what you're going to get but I have learned to free my fishing expeditions in terms of a hypothesis I have this hypothesis that this particular area of the lake is going to be an effective 1 for fishing because there's an outflow of water into that particular area of the lake and that's where fish like to gather to and for hours was the inflow of water the fish like to gather there because it's a new abundant food and that particular spot OK so and if you have an idea that you cannot know in advance really what you gonna find you still frame it in terms of I'm going to be doing this but I societal a hypothesis that the way I'm doing this is going to be more successful vitamin giving example of this it's less and less abstract like fishing and more concrete like after murders so the previous sentence I set this whole thing about boxing so already optimal libraries have emerged as a powerful technique for studying proteins in the cell and on I want to combine after Mercer together with studies of Fox say to them explore boxing is a target for for diabetes OK so I have a hypothesis that if I could discover biting partner Fox say then I will be allowed to do something about this terrible disease called diabetes OK and so on I can't tell you in advance the design of that act of our fund is going to make a whole library about versus like fishing I'm going to just throw them all against Fox said a but I suspect that this is going to be and this is going to work OK so my hypothesis is within this library I could find something that's going to buying to Fox said and furthermore from the library design I'm going to set up so that we're going to be more likely to be successful OK so there has to be a hypothesis embedded in your logic of why it is that you want to do what you want OK but you don't necessarily have to use the word hypothesis OK next sentence next sentence fears on how it fits the definition of chemical biology and you must have a sentence that says that in your In your abstract OK so this in this sentence must say this idea fits the definition of Camby 0 because and then all evil line here OK this is essential your time your abstracts must all include a sentence that says exactly that this but I've been doing this if indeed dealers last for a long time and the year 12 and I've learned that if I don't have a sentence like this will get all kinds of unfocused ideas that came and said no and I know from talking to somebody about book reports that this is still kind of mysterious idea but review the definition can bio and make sure that your idea of squarely targets that definition can buy which is using techniques from chemistry to understand biology at the level of Adams and bonds can make sense OK let's talk about the most important sentence of any proposal this is the sentence that if it's a good 1 this'll get you funded every time and I guarantee you this trick works not just as an asset not just of funding agencies this legal work with their parents and from and those your major funders these days I know OK so let's talk a little bit about that last sentence this last sentence in his arms and 1 that I like to call the payoff can short the payoff sentence is if this idea hits a home run here's what's in it for you here's what is new were meeting society is going to be from that if every expectation that I make it every hypothesis that I propose turns out to be correct here's what you get to benefit from a page so this is the 1 where you imagine a home run now deliver OK Kate what happens what results so imagine a home run and then what results science getting all jammed together once offered on board can makes sense so every abstract is going to end with the payoff this is easily the only sentence that really matters in our proposals because your proposals at any read by a large number of people I'm not talking about him 128 I'm talking about later when you go up in front of a research review board and you're asking for more funding for you're oil development team or something like that and that last sentence that what's in it for the reader on is really the 1 that gets you funded because oftentimes proposals appear in front of people don't really understand them OK so you got proposals have to appeal to a broad audience and on typically proposals are red by groups of 20 people might be 20 people in front of you between you and the and the check and this many there's 20 people are trained in other areas they're really smart but they might not know very much about Fox said they might not be to evaluate whether or not boxes in the target for diabetes research however they definitely need to be able to understand this payoff of pain and a really has follow that it's going to be useful OK so you don't want promise the moon if he can deliver them a peso payoff sentence for our hypothetical proposal might be something like 1 inhibiting Fox a with enough to merit which could provide any motel at 4 a decreasing surges our blood sugar amongst diabetic patients appear now would be useful right that would be extremely important potentially for diabetes treatments OK but I'm not going to say it's going to cure diabetes if I can't deliver a cure for diabetes if you promise you know a cure for cancer or something in a disease you better be able to back it up or else on the reviewer reading a Cisco stock holdings Noah's or his business regularly like Where's my cure for cancer I thought you promised me a cure for cancer I don't seem cure for cancer this might be nice and all that Helsinki anyway right you get ideas so you have to on you have to do have to build to deliver what your promising but on other hand you don't want under promise because this is really the part where the you know the person at the other end holding that the big Daggett cash decides whether or not they want invested you make sense OK this is totally formulaic the formula I'm giving you this abstract format that works for all kinds of proposals it works to proposals that appear in front of venture capitalists it'll work in front of proposals that appear from your parents it'll work for any sort of a group of foundations and or group of people holding money I know because of the formula used to obtain I want you to do that which you follow this formula is well prepared for this class to strike trustee of works and other of any questions about this abstract sure and I mentioned in my view can you and yet some of them back again and I think it's going to do have happened in the look at the question of in 1 evening just Yasmin very wide OK I say yes the Thalys
asking for why what happens if mind of a background is very similar to the background that appeared in the proposal .period not the proposal in the journal article I would say .period another Journal find another sentence 1 the big picture said that big picture sentence has to be your interpretation of why you think it's important not why some of the scientists working at Johns Hopkins thinks is important OK so you have to be spending this to fit your own interests OK so for example if the Journal article starts with the sentence 2 million belong the afflicted with diabetes this year then maybe you wanna say army 200 thousand new cases of diabetes can be diagnosed in next month during the Internet he turned it around right end you you focus on something you think is particularly it and actually now they think about it if your target is this thing that's going to moderate budget may be 1 say you know and 10 thousand diabetics are going to have to have implications of their limbs because of complications from diabetes right see you basically reinterpreting this big problem and focusing on some aspect that you think is important because it's your ideas that I care about not somebody else's ideas and along those lines on the payoff over here and I want your ideas for where the payoff is going to be useful OK why is this going to be helpful for someone reading this you might consider funding it OK on final thought there was a great question other questions so I've mentioned this before in an e-mail and I just wanna reiterated the very best proposals from this class I will submit to the UN campus writing coordinator and I've been pretty successful at getting a convincing the campus writing coordinated that my students are really extraordinary writers and so I've been really successful at getting citizen this class of awards the writing awards which is nice to get add that year CD and I think even cut you a check pesos a rare time that the region's the University California will give you money if you're successful so I'll be on the lookout for the very top 2 or 3 proposals coming from this class because I really contend that the top 2 or 3 proposals from this class of good enough that I can put in front of the National Institutes of Health and I bet they would get funded through that I now have this also of it every year .period when I get those teaching evaluations back someone says Professor Weiss is just fishing for new ideas and I I promise you that is not the case out of it so my laboratory is stocked with ideas for the next 20 years you can ask Miriam a critical they will assure you that I'm always driving them nuts with some crazy idea I think of all the way into work and so on there is there's no way that no matter how brilliant you are going to be scooping up your idea and then you know running into of the life we gotta do this the judge's ruling that said don't worry about that give me your best ideas show your best ideas and it's a bad strategy to hold back your best ideas on because you're afraid someone's going to scoop them pet ideas are a dime a dozen if you're smart enough to come up with good ideas you get smart enough to come up with 1 good idea is smart enough to come up with a dozen more good idea OK so give me your best idea of became don't worry that someone's going to end up scooping you if you do you get to claim some some status right is able I had that idea 10 years ago about that but I took him 128 with that crazy guy and I you know here's my report I got today let us on and so you know maybe that person goes on to win a Nobel Prize in new look cool because you thought of the idea 1st event but I don't hold back .period don't worry about getting scooped anything like that of the truth is out any proposal that you you do you're going to have some situation like that and I if you're starting a new company or something like that sometimes you sign up non companies signed confidentiality disclosure agreements by as CPAs in advance with the people you disclosing ideas too but obviously I'm in science especially in academic science were consciously talking about ideas even with my closest competitors my closest competitors I will tell them exactly what we're working on the not exactly I might hold back some key details fall all certainly tell them the general area that we're going to be Michigan right all the like yeah we're going to be on the spot a lake I might not tell them exactly what Laura using credit lines but I'll tell them what we're going to be doing right so I I want you to do this same don't that messed I cannot wait to read this is 1 of the real rewards of the year I love of hearing about your creative ideas it really is invigorating it's really did and so anyway I'm looking forward to that next Thursday the questions about the cement is like that OK um I will get those back next Thursday and it'll take me a week or so to process them all be in Brazil from Friday onwards next week and so there will be at you won't hear anything from me for a few days don't panic on medium all along the beach in Brazil defeated there I will be on the beach of the meetings but I will be reading lists of the abstracts on the plane and that by the time I get back all of them all comment on for you yet yet actually I'm so glad you asked OK so the easy part of this assignment is thinking the creative idea but that's the easy part the eureka moment and the hard work is where digging into the literature to see if someone else has already done that idea and it's essential that you do this you must do this so what I do is when I think of some idea the 1st thing I do is I run the moment that no 1 had run my laptop I put myself and I typed into Google do quick Google search and see what else has been done in that area and then dental departments searches and I'll change the wording around all day more searches that's the hard stuff OK so they give idea that's like 5 per cent the much harder stuff is doing all the background reading to make sure that it is an original it is essential that you propose an original idea if it is not an original idea I will give it back to you on underrated OK and I'm going to ask critical and Miriam to do Google searches of everyone's idea OK they will do a quick Google search and unable tell me if it's not an original idea that's already been done it's going to be returned to you operated upon a sucker that means have to start from the beginning a case so it's really important that you knew that they stressed that any other questions yet absolutely effect you will effect it's absolutely mandatory that you change your idea based upon my comments based upon you reading it you do etc. and what I'm going to do is on a given back to you but I might ask you to hang onto it and then turn it back again with the proposal at the very end because I want to see the evolution of your ideas in response to my comments a case somebody tell you and you have a new this idea would be a lot better if you went in the other direction like there's a new type of actor recalled em on a display you should look into that and so on be looking for a proposal then that is responsive to that suggestion OK and I'm give points for being responsive to the suggestions or take off points for being unresponsive OK so yeah there's going be considerable changes between now and when the time when the final proposal submitted in fact summer you're going to and that is totally trucking original 1st idea and coming of something new and that's fine too OK any other questions OK brigade again look forward to reading as I let's get back to proteins in all things protein related but I want to be who we surveillance Fidelity's things such as
quickly summarize what we saw on Tuesday as I told you on Tuesday I introduce you very very briefly to the 20 naturally occurring amino acids and I'd like you to memorize the structures the abbreviations their names on we talked a little bit about have peptides can make effective pharmaceutical lead compounds furthermore when the cycle lies when they're in and C-terminal joined together in a ring to form a ring the resultant cycle eyes peptide a cyclic peptide is amazingly stable even an I had the stomach even in this very courteous rich environment of the stomach it turns out this is actually fairly generic it seems to work really well and I cycle times are actually emerging as an important pharmaceutical class of compounds and then we looked at how peptides can also be used as lead compounds to develop small-molecule therapeutics is OK and the next topic was what we looked at a technique called chemical ligation for stitching together small peptides into much larger proteins this actually works very pretty well that actually this is a good technique the nice thing about it is because the on peptides are chemically synthesized you can include unnatural amino acids pretty readily and that allows hypothesis testing rate if you replace it say I'm a hydroxyl functionality with the CIA 3 functionality maybe even test whether or not the hydroxyl is donating a hydrogen bond and you look at issues like the Florian based hydrogen bonds OK take a look at stuff in the unique ways using unnatural amino acids that are introduced using chemical synthesis and along the lines of chemical synthesis we very briefly reviewed the cargo Diomede Coupling reactions that you learned about back and soft organic chemistry and I suggested that those were unfamiliar to you you might wanna go back and review OK and then finally we ended on I'm talking about how proteins spicy can result in a spontaneous removal of Indian team using a theory similar mechanisms the it's any questions so far variation I want to go and talk next
about we just get on
and I want to talk next about conformational analysis
which is about I'm trying
to understand why it is proteins adopt specific configurations last time for example and
we learned about helping helices and we learned about
beta-sheets and I haven't really told you of to much more about how it is that the same What are the forces that are driving these structures into these particular confirmations and on
before you do this a couple of more quick words about beta-sheets beta-sheets come in 2 flavors and they can be either parallel so the strands are running from 1 end terminus on the left C terminus on the right and left the terms of bright these without parallel strands OK so nervous and terminus is on the left C terminus is on the right and this is this trend is going in this direction the next round below going in this direction going in this direction and on the other hand more commonly beta-sheets can be found in antiparallel directions and I'm saying more commonly because if you think about it there has to be a very long linker between the C terminus on this side and then terminus on this side of all this great stuff that's really lot OK whereas in antiparallel fashion the baby she can very neatly Halverson terminus 1 and a little later than the lead to the end terminus leading to the C terminus and so on and recall that in to see convention that we use to describe peptides and that also illustrates other direction al-Attiyah of these spirits there a dying from enter terminus see terminus which is how we read protein structure OK now on something that's interesting about this as well noticed that the hydrogen bonds at slightly different angles between the parallel beta-sheets antiparallel beta-sheets it turns out that the nature of quarters flat surfaces flat surfaces are very very rarely found in biology for tip more commonly flat surfaces are Kirby and I'll tell you exactly why beta-sheets occur via moment but but before we do let me just note that of
beta-sheets fold up In 2 and structures services that aren't perfectly flat so I'm very commonly beta-sheets will fold up into this state of barrel is certain antiparallel are parallel beta-sheet OK good Yeti parallel right because this 1 the arrows going down here and this is the next step strand is going up in the opposite direction down in opposite directions in opposite direction etc. and that's what we're going to call the antiparallel OK so this is pretty common .period beta-sheets conform into these barrel like structures of these barrels can be fit into plasma membranes of membranes on the surface of the cell they also used very commonly as binding proteins and even as active sites for but kept catalyzing reactions and stuff can happen either inside of the data should be in a barrel but also on the outside of the data barrel as well and I'm OK here's an example of a parallel of beta-sheet over here on the right notice all the areas are pointing in the same direction notice that it too is Kirby it's not forming a perfectly flat beta-sheet instead he sings like to curb all explained that more in a moment even this 1 that looks relatively flat of an immunoglobulin domain curvy rate curvy its curving out slightly toward says I realize a wall to said but on another here and a know beta-sheets they're called sheets but they really look a lot more curvy than that OK questions about initiates 1 OK more
pictures of beta-sheets I love looking at pictures of proteins and this said to me it's like visiting with those zoo or something this is a beautiful OK so here's 1 this is a nice idea of the beta Sam which KBC to beta-sheet stacked on top of each other like slices of bread on notice how palace forms kind of propeller like twist over here this inside here is not empty the side chains are sticking in over here and over here and make the sheets are packing together to form a nice score with each other the side chains are tickling each other from 1 sheet to another and the chains informed packed together to form a core that consists largely of hydrophobic residents will take a closer look at that and moment OK actually it's right here OK so here are the side chains of the beta-sheet noticed that the side chains are perpendicular to the sheet this is due to something called a little extreme which will look more closely at in just a moment of pain so bear with me in about 3 minutes we're going to know young like to tell you what a little extraneous but notice the consequence of a world strange is that all the side chains are sticking down peril perpendicular to the beta-sheet there like Leaves of Grass is better blades of grass that tennis sinking down and then this beta-sheet down here as well sightings that sticking up to grasp onto the side chains up there OK so the beta-sheets tend to be Kirby they had the side chains perpendicular to the beta-sheet ready for interactions OK 1
final element of secondary structure proteins that I want to introduce you to the turns turns were
found at the ends of
each 1 of these sheets each 1 of these strands OK 7 years a beta-strand down here and this is a turn and leads to another strand so each 1 of these strands are connected together by loops and turns and let's take a closer look there's
2 kinds of turns out of balance a 180 degree turn that called Abita turn case in this case and 1 strain comes down here it turns around 180 degrees it heads back on and the the other turned it's kind of like a right-handed turned case comes in here and and then it turns and this is called a diameter and they are sorry this is yet to right to on notice that these tournaments feature 1 in only 1 hydrogen bond there's other elements that stabilizing the turn largely from the strength of these interactions of the strands over here and and there's residues over here that critically on steeple together the turns in case you have to sign genes interact with each other such as to the phenylalanine citing last time on Tuesday I showed you how the PPE side-chain interaction was 1 of the strongest and most over-represented in the population of protein structure said somewhere over here it's likely that you have something like that between 2 and all groups of phenylalanine side chains and so this 1 hydrogen-bond is not the world's greatest of on a common data of this sort of this term but you know it's not so strong that force the turn to happen but there is other residues that played more than a supporting role in assuring that the turn of the year is on it is this happening OK now here's the thing because there's only 1 hydrogen here would he think happens to all those other hydrogen-bond donors and acceptors what do you think the yeah OK into the the question so you have 1 hydrogen bonds so that has except the and donor tied up but then you have all these other donors and acceptors these guys are available to do things what do you think they're doing yeah Chelsea suggested that these are interacting with other proteins and in fact that's why these terms are often found at positions that need to accommodate other binding partners you have all these extra hydrogen-bond donors and acceptors they're looking for business they're hanging out there they don't have anyone maybe they can pick up some other mining partners furthermore because the turn itself is set only by this 1 hydrogen bonds that means that the term can be relatively flexible In the regions of secondary structure this is the most flexible region of the protein and so on oftentimes in of of the areas of of protein structure that accommodate large numbers of different binding partners we find these terms because they can go and change they can move around and be flexible enough to accommodate different sizes of finding partners yet at the same time we have lots of hydrogen functionalities hydrogen-bonding functionalities that and then donate to the binding partners come and the
mission an example of this this is on at the interface between 2 proteins that are interacting with each other and notice that there are a bunch of these are loops that reaching up to touch each other OK that's fairly typical we have to binding partners that are interacting with the sort of looping regents maybe regions are flexible enough to accommodate diverse finding partners it choose me another example of founded bodies and we'll look at it that that at the moment that makes sense OK I'm now that turns obviously requires some amino acids turns like these from requiring that don't mind being taught quite quite dramatically right effects a loop back over here you need some amino acids that can handle that kind of a big turn and not all amino acids are so accommodating with that kind of thing and when we look at trends in the distribution of amino acids we find that some amino acids that are better at making these terms than others and this also applies as well to beta-sheets the things that like to do turns not so good at making strands of a beta-sheet where there the peptide has to be extended wine right of thing once determined not to be so good in the middle of the beta-sheet became and so for
this reason and we can classify amino acids as common as Hewlett's former Hewlett's breakers are present in Quayle's etc OK and on when see candidacy see this way back here I wasn't sure what to put the slides together his election on my own prescription for 4 glasses working really well today I could see that really can you see this as well OK get I'm OK so the red numbers larger red numbers are on not higher distribution of amino acids in these different structures a case for example Ballantine is found very commonly enough helices glutamic acid very commonly offered helices and other ones like lysine not so much a K glycine might be found more coils and beta-sheets glycine isn't so good because it's it's too flexible glycines also found very commonly in the desired turns that I
showed on the previous slide OK so it turns commonly have a glycine over here and there probably never hear so cheeky it's a very common motif interns glycine doesn't have a side change can very readily bands and bent to accommodate this this dramatic 180 degree turn but on the other hand that had been the ability not so good for beta-sheets also not so good for property helices and
that's what you see in this example over here Friday has a number of . 4 7 has a very very low number of propensity OK what else can I tell you what I noticed that the amino acids that have carbons of beta carbons not found so often in our facilities Albert helices recounted twisted Ott curled up and out of the bidding functionalities pass evaded carbon tend to run and to those who think that Quayle's about USC so instead these tend to be lower than the large side chains tend to be overrepresented in our beta-sheets had more commonly found in beta-sheets so this is things like phenylalanine trip the tyrosine these big aromatic residues more commonly found in beta-sheets it makes sense in don't memorize stable but get ready to kind of prepare to explain some of these trends OK I totally legitimate problem would be for me to ask you so I'm here so you know you know what is the structure of phenylalanine I would you expect it to be more common in beta-sheets in diameter turns or Alpert Ulysses and White accounts right makes sense OK I want to talk to
you in further detail about that kind of conformational analysis and what to do that complemented joined the board of the
OK now OK so we're going to
start off very slow parents start off easy but I'm going to start off with just thing OK so simple unit 2 carbons but I guess we don't spend enough time thinking about anything but let's imagine that you look down on this carbon-carbon bond OK this is indeed a symbol for your eyes so imagine your eyes pointing down this carbon-carbon bond if you did and I you look that's a projection down bond which you would see that it is the 3 hydrogen so 3 hydrogen inside of the methyl group that's closest to you and then we would have the 3 hydrogen ends of the methyl group that's further away it makes sense parents so as the right OK now let's talk a little bit about them How much more energy is required to do go from this case this is staggered the 2 of them versus the eclipsed Casillas rotate on on and on what is the 60 degrees rotate down at the C C bonds pay so if we do this we will then have a hydrogen eclipsing each other when you make when you write when you draw these projections draw them so that you always have the Merc's symbol OK I find it easier to do it that way OK so in this case we relocated down the carbon-carbon bond and now instead of having a hydrogen so that are staggered away from each other there now eclipsed on each other this takes energy can so this is on each 1 of these hydrogen sets eclipsing each other is on the order of a take help formal so that the difference in energy here is something like 3 K Kallstrom and these are estimated numbers and now I'm back in 10 51 AM when he 1st learned about this power this standard was greatly preferred over the collapsed I think it was described to you as being due to moved but being due to allosteric effects right this hydrogen runs into this hydrogen over here and the 2 of them are repelling each other Turns out those hydrogen is a really tiny and Decatur it we need our models of what was happening here each card movie about the size of the balloon and each high the likable people on the side of the liver so these little pimples on running into each other patrons at that's actually not the commonly accepted explanation anymore for why it is that the standard confirmation is greatly preferred over the eclipse confirmation instead but what we find is actually it's due to a hyper conjugate effect and ultra attempt to draw that for you here so I'm in the staggered case that's what I said this is a differ representation still of the staggered case OK so here's that 1 hydrogen there's 1 coming out towards us going down this 1 going out to it's the back going down up here in the back 1 like that 1 had so this is preferred because there is actually a very tiny residents cultivar conjugation and so what's going to happen is the following that gives each plus up here and H minus down here said this is the world's lousy years of residence structures it's 1 that probably hasn't even entered your radar was not even on your radar effort consideration but it happens to a nearly tiny but appreciable extent in order for this resonance structure to take place for the resonance structure to stabilize things this idea and this hygienic have to beat and tied to each other and you can only have this entire configuration in the case all of the staggered confirmation of that they pay doesn't happen the clips confirmation OK so for this reason 1 amino acids and proteins will also adopt in Yantai configuration where possible OK they're also going to be following a hyper conjugated effect now I can tell you that they give up her conjugation and will eventually start to numb your mind and and kind of afford the brain regions requires do magic crazy brainpower to think about all these resident structures so it's simpler to think about it in terms of spirits this spirit arguments also correct OK but people also will lead you to the cracked exist answer but keep in mind that the real thing that's underlying this
year that business is actually a hyper conjugate of effects OK until things get much more complicated as we start building up from 2 carbon molecules OK let's get started next with butane tanks of butane can start off as I'm in entire confirmation the at sign Of the case so here's a butane 2 OK sorry we're going to do our projection down this carbon-carbon bond here and this 1 is coming out toward us there's a hydrogen here methyl groups here N and say sorry I left group here hydrogen nitrogen this this this this and this and this and this OK so 1 possible confirmation of butane there's another possibility again were going to rotate in and around this carbon-carbon bond analogous to what we're doing up there with the FAA and in this case a right to be rotating 120 degrees here and if we do that and what will happen is we'll have a confirmation that has that looks like this but has rotating with and then always keep 1 of these constants OK and again the projection here now looks like this where we have our method gripped hydrogen and hydrogen and now which of these 2 is more stable 1 left to 1 on the right OK the 2nd include all of the right reiterate hand all they were laughter is reluctant to allow gay rights have carry the day I'm so yes indeed this 1 is more stable it's called in Yantai of configuration this 1 over here is less stable because these 2 methyl groups again running into each other this is called douche configuration OK so and this happens to be less stable by on the order of but 1 cake help mold OK so this 1 over here it the requires an additional 1 k cal all 10 so we're possible we're going to try to find entire confirmations of or amino acid side OK so we've seen evidence we seen beauty let's build up to 1 more complicated let's go up to paintings on pentane gets much more interesting because it turns out that in addition to the gals configuration you can get 1 more confirmation of that pentane that's relevant so here's pentane here's 1 possibility knows that there's 5 carbons there this is 1 possibility fears from another possibility and which of these 2 is preferred 1 left 1 on the right right hands on their right hand takes a radiance all Arab Lieutenant lieutenants are I opinions divided it turns out that actually the difference here is on the order of freedom for key Cal's promote again by the way where I put the numbers those numbers are at a higher energy OK so this 1 is going to be greater in energy verses from I would say 3 K calls kind of depends on what we start with on the reason it is easy to methyl groups are now banging into each other very strenuously OK is up here this methyl group is nicely out of the way this is going to be called a certain pentane confirmation of cancer there's terms that were going to be using staggered eclipse douche versus on time and then finally sent pentane verses of nonsense content of Henderson pentane is pretty big at somewhere between 3 and 5 the Council is really bad OK so proteins are going to do everything possible to avoid running into this and make a run into this 1 and it would be the branched amino acid so this at its heart is what's driving the formation of about the Ulysses and beta-sheets what's going to admit allows some amino acids status beta-sheets better than other amino acids and um when we take a closer look at the case of these the terms so comfortable now after the the definitions of these terms because calibrated in terms of numbers OK well that some of the started that the OK so we've looked at eclipse versus staggered so but that
being can and fears of some the summit on numbers but this is we didn't talk about eclipsed butane that's used to my mind by Kallstrom all this is never going to happen is so large that does even enter the equation case 0 I think we can all agree on the clips and butane horrible OK at Dallas butane higher by about 1 K culpable .period 90 cultural great either but in time lowest in energy OK so next time I want to look just very briefly at a few amino acids it turns out that we can very readily project on which amino acids are going to have preferred configurations OK and fortunately I have to go back up again sorry realizes a lot of ups and
downs but I'm OK when we take a look at the amino acid viewing the Elian has an isopropyl side chain and so it turns out that the alien actually will adopt 1 and only 1 confirmation that will largely adopts 1 confirmation OK so I'm what I'm going to do we just think about this for a 2nd OK so we're always going to have NH over here ,comma deal over here so that will be a backbone part of the some talking about these things not just dealing by itself but the lead in a bar in the context of being a protein OK so has an separable side so on 1 possible confirmation of the Is there this is the kind yes there's 1 other To ensure yes OK so the angle defined by see Alpha to see data is called Taiwan in going to the rotating down the sky ones as we start looking at the amino acid side it's OK so let's imagine rotating 120 degrees down this kind 1 angle OK so this angle here in blue if we do that will have of these 2 CH 3 so the Runcie that rotate 120 degrees down Kyle 1 1 methyl group is to be sticking out over here 1 was pointing down we rotate 120 degrees 1 sitting off to the right ones pointing down can go from here you rotate 120 degrees you got here make sense OK what is the difference in energy between these 2 any difference and energy the money the I'm only lawyers there is the guests and the answer actually involve the use of the same was true questions sorry right because they both have to be the same number of vouch interactions right so this 1 over here has 1 -dash interaction but this 1 over here also has found 1 -dash interaction and I'm not even worried about these 2 methyl groups down here right OK let's do 1 more rotation that same idea rotating around the high 1 angle so again in blue this last 120 degrees again around this high 1 ends up and if we do that OK so again we keep about constant if we do that we're going to go from a situation where we had 1 method groups sticking up on the right 1 going down we rotate and now we have to method ribs sticking out 111 year OK so higher energy lower energy do you a day ago I hear a lot of guessing OK so up here this guy over here is subjected to gash interactions 1 there and 1 here so I really doubt interactions down here how many gas interactions are present douche butane interactions are present in this molecule to 1 to any others OK so which ones hiring energy topped 1 or 1 by how much 1 Calvin OK so this is lower will call this appear higher will say lowering energy lower by 1 cake help promote . 9 1 relatively similar so when we look at structures of proteins we find that this the lean side chain is going to be predominantly in 1 confirmation is going to strongly prefer this confirmation forces other confirmations noticed that if you rotate a little bit further they can result in eclipse interactions is eclipsed actions were so high in energy I'm not even going to consider that just thinking about whether you have -dash mutations in trying to minimize the number of gas attains means that the feeling will prefer 1 and only 1 confirmation makes sense proteins are a massive minimization of interactions like this couch butane and 1 of the most dominant is something called a little extreme and that's what I want to talk to you about next OK so let me 1st show you what a little extraneous so that I would see little
extreme results from I'm an OK so a little
extreme results from rotation around the bond that's a little elect to carbon-carbon double bonds this is the AL functionality it's 3 carbons to of formula carbon-carbon double bonds no rotation across the carbon-carbon double bonds here are too the ones and what happens is there's 2 kinds of a look strange the numbered there called 81 3 and the other 1 is called B 1 2 in the case of a 1 to strain to functionalities are are running into each other no 1 from the other that 1 that's attached to the middle carbon of the Al upon chirality and 1 that's attached to the on the other side of the other side of the 1 that's attached to the carbon it doesn't do any carbon-carbon double bonds OK now there's free rotation around this carbon-carbon single right the carbon-carbon double bonds is fixed he can rotate but the single bond is free rotated so it's going to rotate away From this 81 to interaction notices 1 too because this is carbon 1 this done until they want to a little at 1 to restrain this is huge this is like a cake :colon a half or so so as it rotates it can actually rotate into a confirmation configuration such as this 1 up here were now it has another then this case methyl group Benny into are means 2 are going to be approaching each other in space kind like this in pentane interactions and again and this is going to be on the order of 3 k cal from all of deleterious energy Bloomberg proteins take this kind of thing so instead what will happen is preferentially you'll get rotation around this green coloring double carbon-carbon single bond and that rotation will push the hydrogen into the same plane as are punctuality hydrogen no small it doesn't is not subject to the solo extreme on the other hand by doing this you avoid having any functionality pointing down here that could be interacting with anything that's on this carbon-carbon bond rate here OK so you avoid a 1 2 strain and you also avoid alike won 3 straight and again this is 1 3 because this is between carbon 1 and carbon 3 8 1 2 3 makes sense OK so now you're probably wondering how could this possibly affect proteins this amendment is England is type of lawyering yes I don't know if you go in there and then yes so far yet so actually psoriasis is the other indirect letter from capturing assembly will you get points for refining mistaken about that stuff frustrated that OK but for that was little more closely thank arrested and here are some examples OK so in this case over here here's a punch has met groups and in this case we have the smallest functionality next to that methyl group of waiting Oleg strains over here for rotates up if the rotate around the step to methyl groups next to the method of next to the and the starting methyl higher energy by 3 . 4 K Kallstrom all in the 2 of these are right up close to each other that's like this in pentane interaction which we know it is about I'm highly disparity 1 over here a similar things OK said even when you have a hydrogen attached to the carbon the carbon-carbon double bonds you can still invoke some of some strain as well and was not shutting off OK makes sense she's sorry I think it's shutting up the yeah right should a stop working entirely useless now but
a little extreme it turns out dominates the protein backbone because there's a partial double bond character for each 1 of those Adam adds that is joining together the amino acids of the protein backbone and so it turns out that the partial double 1 character is actually very common like 40 per cent of the time I'll think you had so much think you so here's here's a regular Ahmed and you can get rotation around this carbon-carbon bond every year totally free rotation thank you but 40 per cent of the time this animated is going to former residents structure that gives you this nitrogen carbon double bonds and so now you start getting into Lott's trading between this oxygen up here and then this hydrogen over here so this confirmation is strongly preferred but if you rotate around here you can't have a functionality up in the same playing as oxygen due to that a look straight so the backbone of the protein itself is not always eagerly flexible instead it's going to adopt at each 1 of these on the bonds 1 and only 1 preferred configuration this really important concept this is why we keep seeing beta-sheets and help losses this is why proteins on holding all over the place and giving you all kinds of crazy stuff it is only 1 confirmation that's going to come out of this and it's due largely to the Selic strain With this makes sense concept of the takes critical but OK here's
a here's what this looks like so this is a histogram of of angles for I'm a protein and these angles are defined as the angle between nitrogen and carbon is being on us that they buy angle and the angle between the Carbondale and the Scialfa common that's a sign angle and the graft here are the flight angles and here the sign angles and in colors this is where we actually find proteins so if the spaces in white over here we've never found any protein this naturally occurring there would occupy the space by the way this map was made up of originally by the continent and hold or on the continent plot and its use very commonly to check the correctness of structures of proteins case so what we look at this week finds that there's 2 major mountains that dominate in this histogram NY these sigh and sigh and by angles defined the secondary structure as that regular right handed out the Helix that I been showing you less commonly you can also get a left-handed opener but this 1 is going to be the dominant 1 we also find beta-sheets again with a certain sigh and find angles and said because the science angles are set by this they want to strain on this 81 3 strains there's very little room for free rotation and this is why we only see tuned to Texas secondary structure all of this stuff was worked out by the great Linus Pauling but always before protein structures were salted just slightly before that I'm here despite true brilliance and just thinking about how molecules rotate in space makes sense the questions about this right will look at more complicated protein
structures on the 1st kind a confirmation I wanna talk to you about our disulfide bonds and proteins really it more complicated so there are die sulfide bonds in proteins form a guy he took form these are 2 sulfurous the little shiny gold balls 2 solvers their bonded to each other to form a sulfide and noticed that the dying usual angle here is nearly 90 degrees these form these tend to prefer a 90 degree for there are 2 conformations a the right hook and a but left twist OK so right hook left West of I have reversed but that's idea so to possible cooperation both with 90 degree died he July Ingalls and you could see that very clearly by looking down the vessel for sulfur born of that I sulfide so these are going to help to stitch together and provide spot welds to hold together proteins that not all are common a very large protein might have 1 or 2 of these are maybe as many as 5 but it's not like they're going to be you know every of amino-acid hazardous sulfide these are relatively rare and they are because the covalent there good ways of billing blocking particular confirmations of proteins OK so this is
a spontaneous process deformed sulfides that occurs if you leave out files on just sitting on your bench they will go to form die sulfites pretty readily by oxidation reaction using air as oxidant to former sulfide take in biology in cells but there is a source of while Wyoming where the slip otherwise slippery SH functionality is attached to a larger handle that's useful for enzymatic binding and in
practice I sulfide exchange happens very quickly and very readily and this report a way of reducing files found in proteins OK so I think I'd now introduce you to all the elements of a conformational structural proteins were now ready to look at the proteins themselves chasing now you understand all of the elements that are kind of the toolbox for building large protein structure let's put them together OK so 1st
in protein structure terms there are 3 levels of on descriptions of protein structure of the primary sequence is simply the sequence of amino acids typically one-letter code the secondary structure is on the listing of these as helping Ulysses and beta-sheets Mucha exactly what not being
shown here about the need to show you on this 1 a primary structural amino acids secondary structures LP helices the sheets on these oftentimes fold up into discrete domains and then these domains fold up into larger structures called tertiary structures which in turn can interact with other structures and non-committally or covalently to resulting quite eerie structures and an even larger biological assemblies OK so we now understand how to get the probe the primary structures by forming bonds either using them ,comma diamonds or the riders some and we now understand why it is that secondary structure forms and our next step is to understand tertiary and Quaternary structure and I think I'm going to take the full 2 minutes to try to go as far as possible and I'll pick up whatever I don't cover on Tuesday I'm OK so individual domains tenfold independently that will be a working definition domains of proteins regions of proteins that you can clip out of the larger proteins and they can hold up without the large approaching around a typical domain is this Evita sandwich wage structure called an immunoglobulin demand too initiates the stacked on top of each other this time folding is driven by hydrophobic collapse the interior of the state of Salinger's is hydrophobic and exterior is Hydra Village and that's a concept we've looked at in some detail a couple of times before if
we look at the most common protein domains as listed in the human proteome what we find is that there are a few that dominate over others and so I'm going to do is I'm going to organize the rest of his lecture according to the most dominant structures cases starting with ball goal
proteins zinc fingers are easily the most common we've seen this before we talked about case transcription factors case so in this case and the structure is held in place by the zinc ions and there's a nice alpha-helix on 1 side OK let's stop here when we come back on Monday lot Tuesday will be talking more about protein structure and then on to protein function
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