mmvvmm@mixcom.COM (Daniel Offutt) (05/09/91)
I have found descriptions in the literature of various applications of computational methods to protein *folding*. But I have yet to discover an article concerning the application of computational methods to protein *design*. Perhaps this should not be surprising, since a solution to the folding problem appears to be a prerequisite to a solution to the general protein design problem, and the folding problem appears to be computationally intractable today. Is this an accurate summary of the state of the art in computational protein design? If not, can anyone point out some articles on computational protein design worth reading? I would be interested even in experiments with designing much-simplified "model" proteins. Daniel Offutt
toms@fcs260c2.ncifcrf.gov (Tom Schneider) (05/14/91)
In article <719@mixcom.COM> mmvvmm@mixcom.COM (Daniel Offutt) writes: > ... I have yet to discover an article concerning the application of > computational methods to protein *design*. @article{Blundell1985, author = "T. Blundell and M. J. E. Sternberg", title = "Computer-aided design in protein engineering", journal = "Trends in Biotechnology", volume = "3", pages = "228-235", year = "1985"} @article{Wetzel1986, author = "R. Wetzel", title = "What is protein engineering?", journal = "Protein Engineering", volume = "1", pages = "3-5", year = "1986"} @article{Pabo1983, author = "C. Pabo", title = "Molecular Technology: Designing proteins and peptides", journal = "Nature", volume = "301", pages = "200", year = "1983"} There must be more recent papers than these, perhaps you can use them as the basis of a search. > Perhaps this should not be surprising, since a solution to the > folding problem appears to be a prerequisite to a solution to the general > protein design problem, and the folding problem appears to be computationally > intractable today. Is this an accurate summary of the state of the art in > computational protein design? No, there have been several attempts reported in the literature, even a case of a the construction of a catalytic protein. Sorry, I don't have that reference, but I think there was a paper in nature within the last year. Dickerson, I believe, has been working on constructing bundles of alpha helices and beta sheets. Also, the the emerging field of nanotechnology, it is recognized that it well may be easier to design proteins from scratch than to figure out how they evolved in nature. Look at the sci.nanotech news group for discussions. @article{Drexler1981, author = "K. E. Drexler", title = "Molecular engineering: An approach to the development of general capabilities for molecular manipulation", journal = "Proc. Natl. Acad. Sci. USA", volume = "78", pages = "5275-5278", year = "1981"} @book{Drexler1986, author = "K. E. Drexler", title = "Engines of Creation", publisher = "Anchor Press", address = "Garden City, New York", year = "1986"} Tom Schneider National Cancer Institute Laboratory of Mathematical Biology Frederick, Maryland 21702-1201 toms@ncifcrf.gov
pauld@stowe.cs.washington.edu (Paul Barton-Davis) (05/17/91)
In article <2158@fcs280s.ncifcrf.gov> toms@fcs260c2.ncifcrf.gov (Tom Schneider) writes: >No, there have been several attempts reported in the literature, even a case of >a the construction of a catalytic protein. Sorry, I don't have that reference, >but I think there was a paper in nature within the last year. Dickerson, I >believe, has been working on constructing bundles of alpha helices and beta >sheets. Also, the the emerging field of nanotechnology, it is recognized that >it well may be easier to design proteins from scratch than to figure out how >they evolved in nature. Look at the sci.nanotech news group for discussions. On the other hand, there are a number of well known cases (I've been out of research in this area for 4 years, so your guess at names is as good as mine) of: 1) proteins of very similar sequence folding into rather different conformations, even at the secondary level (helices and sheets) 2) proteins of quite different sequence folding into rather similar conformations. So, with a perspective that's a little stale, I would have said that Tom's description doesn't do the problem justice: we don't understand how proteins fold, whether they are synthetic (ala Drexler) or native. Although there are a few successful examples of predicting what will happen to a given protein when it is allowed to fold up, they so far seem not to have elucidated any fundamental understanding of the process. Until that happens, it may well be that any further successes will continue to represent good luck rather than any engineering capability as wanted by the nanotech folk. Perhaps someone with a newer perspective on the problem of protein folding could comment on this, if any such person actually *reads* this group ! I worked at EMBL in the biocomputing group there for a year, but got too hooked on computers and came to the conclusion that the protein folding problem is at least a decade away from being solved. -- Paul Barton-Davis <pauld@cs.washington.edu> UW Computer Science Lab "People cannot cooperate towards common goals if they are forced to compete with each other in order to guarantee their own survival."
sjhg9320@uxa.cso.uiuc.edu (Maximum Slackness ) (05/17/91)
I'd kill to PostDoc in a protein lab where I could spend 50 hours a week at the bench and 30 at a Computer. The people I am familiar with that take a genetic approach are all Computer-innocent and the few computationally oriented people I have discussed the problem with are completely ignorant of the biology (e.g. Post-Translational Processing). At any rate, there is no way predictive, general models can be made until the biologists nail down considerably more of processing and assembly pathways of proteins and get a better handle on how different cytosolic proteins interact with each other and how membrane associated proteins interact with their attendant lipids (once they determine local membrane assymetries for each individual protein.) -- No matter what you do, somebody always knew that you would...
wrp@biochsn.acc.Virginia.EDU (William R. Pearson) (05/17/91)
In article <1991May17.005953.12252@beaver.cs.washington.edu> pauld@stowe.cs.washington.edu (Paul Barton-Davis) writes: > >On the other hand, there are a number of well known cases (I've been >out of research in this area for 4 years, so your guess at names is as >good as mine) of: > > 1) proteins of very similar sequence folding into > rather different conformations, even at the secondary > level (helices and sheets) > > 2) proteins of quite different sequence folding into > rather similar conformations. > I do not believe that there are any "well-known cases" of proteins of very similar sequence (>50% identity) folding into different conformations. I would be very interested in evidence to the contrary. Often, when X-ray structure people mention very different structures, they are referring to the orientation of the side chains or loops, or perhaps a very high precision statement about exact location of the alpha-carbons. Alternatively, they may be talking about a very short piece of sequence (4 - 5 residues) in a larger, unrelated protein. In the case of short sequences in unrelated proteins, it is not unusual to find the same sequence in different secondary structures. For "proteins," however, those that are similar enough to be considered homologous ALWAYS have the same 3D structure. Bill Pearson
pauld@stowe.cs.washington.edu (Paul Barton-Davis) (05/17/91)
In article <1991May17.121858.12141@murdoch.acc.Virginia.EDU> wrp@biochsn.acc.Virginia.EDU (William R. Pearson) writes: > [ stuff from me about overloading of sequence-structure > relationships ] > > I do not believe that there are any "well-known cases" of proteins >of very similar sequence (>50% identity) folding into different >conformations. I would be very interested in evidence to the contrary. OK, I dug out my old copy of EMBL Research Reports to see if it mentioned the ones I was talking about. Look in the literature for stuff on the TIM barrel (triose phosphate isomerase). Chris Sander would be a good investigator name to spot. >Often, when X-ray structure people mention very different structures, >they are referring to the orientation of the side chains or loops, or >perhaps a very high precision statement about exact location of the >alpha-carbons. This is often true. *HOWEVER*, it is frequently these small differences that are critical in distinguishing functionality. One consequence of this is that if there is this imprecision in the relationship between sequence and structure, then although from the point of biological investigation, not much is lost, we do lose the ability to have the kind of engineering capabilities dreamed of by the nanotech folks. > For "proteins," however, those that are similar enough to be >considered homologous ALWAYS have the same 3D structure. Again, I believe if you look up work on the TIM barrel, I think you will find some examples that contradict this, though I'm not sure to what extent. As a philosophical aside (I've been waiting to get this off my chest for years, having been amongst computer geeks and not biochemists), I do think there are some important reasons why we don't understand protein folding and sequence/structure/function relationships in general. The primary one is that proteins and their interactions are not too far above a level where quantum effects are still significant. There are a few papers around in JTB on things like electron tunnelling in proteins, and no doubt other effects at this scale exist also. The interactions between a nascent polypeptide (boy, this bio-jargon is more fun than CS), itself, ribosomes, translational modification factors, the intracell environment, let alone substrates in enzyme reactions, are fundamentally quantum mechanical (as are all reactions). Researchers working on protein folding and protein-XXX interactions (where XXX can be nucleic acids, lipids, water etc.) generally limit themselves, often by practical necessity, to studying proteins on a per-residue basis, with frequent dives down to the side-chain atom level. I consider it unlikely that the interactions are this crude. Proteins, with their magnificent conformational contortions, offer nature the chance to create extremely subtle variations in the physico-chemical environment for reactions. When we talk of protein conformation, we normally talk of the relative positions of residues or side chains. Isn't it more likely that the functional aspects of protein conformation (both finished and during folding) result from precise atom-atom positioning ? If this is true, then it appears to me that we cannot understand protein folding until we are in a position to understand these type of interactions. This is not trying to imply that we can't make significant progress toward understanding, at a gross level, the relationships between structure and function. But just as in DNA, where it increasingly appears that very subtle variations in atom positioning (e.g. tilt angles between base pair planes) give rise to important functional behaviour, the same is likely to be true of proteins. We are very unlikely to be able to begin to engineer *new* proteins until we can grasp how the complex quantum environment created in a protein contributes to its function, and I would guess that that day is several years away. -- Paul Barton-Davis <pauld@cs.washington.edu> UW Computer Science Lab "People cannot cooperate towards common goals if they are forced to compete with each other in order to guarantee their own survival."
sjhg9320@uxa.cso.uiuc.edu (Maximum Slackness ) (05/18/91)
wrp@biochsn.acc.Virginia.EDU (William R. Pearson) writes: > I do not believe that there are any "well-known cases" of proteins >of very similar sequence (>50% identity) folding into different >conformations. I would be very interested in evidence to the contrary. Consider ion channels such as the Axon Na+ Channel, the proton pore of the V-Type ATPases, or lac permease. Scott Howard -- No matter what you do, somebody always knew that you would...
lesher@ncifcrf.gov (Lesher) (05/18/91)
You might want to check recent work by Stephen Kent and Peter Schultz, Graduate School of Science and Technology, Bond University, Queensland, AU. I heard them speak a year ago on "The Total Chemical Synthesis of Proteins: Nature and Beyond." Sarah Lesher lesher@ncifcrf.gov
wrp@biochsn.acc.Virginia.EDU (William R. Pearson) (05/21/91)
> sjhg9320@uxa.cso.uiuc.edu writes: >wrp@biochsn.acc.Virginia.EDU (William R. Pearson) writes: > >> I do not believe that there are any "well-known cases" of proteins >>of very similar sequence (>50% identity) folding into different >>conformations. I would be very interested in evidence to the contrary. > >Consider ion channels such as the Axon Na+ Channel, the proton pore of >the V-Type ATPases, or lac permease. > >Scott Howard I have done some comparisons of lac permease (PIR code GREC) with the sodium channel protein I of rat (PIR code A25019), and while these two proteins do share considerable similarity (16% identity over 232 amino acids), they are certainly not >50% identical, and it is not at all clear that the two sequences are likely to share a common ancestor; many unrelated membrane proteins share about the same amount of similarity. Lac permease does not share dramatic similarity with any other proteins in the PIR protein sequence database, with the exception of a Klebsiella lac permease. So I am not clear what these sequences show. They are not >50% identical. I do not know whether they share similar structures. There are plenty of examples of very distant proteins that share considerably less than 20% sequence identity but have similar structures. Such proteins are usually considered homologous, since structure is more highly conserved than sequence. Still awaiting "well-known" cases. Bill Pearson