Path: utzoo!utgpu!news-server.csri.toronto.edu!bonnie.concordia.ca!uunet!zephyr.ens.tek.com!uw-beaver!stowe.cs.washington.edu!pauld From: pauld@stowe.cs.washington.edu (Paul Barton-Davis) Newsgroups: bionet.molbio.proteins Subject: Re: protein design using computational methods Keywords: protein folding, computational methods, molecular dynamics Message-ID: <1991May17.155433.433@beaver.cs.washington.edu> Date: 17 May 91 15:54:33 GMT References: <2158@fcs280s.ncifcrf.gov> <1991May17.005953.12252@beaver.cs.washington.edu> <1991May17.121858.12141@murdoch.acc.Virginia.EDU> Sender: news@beaver.cs.washington.edu (USENET News System) Organization: Computer Science & Engineering, U. of Washington, Seattle Lines: 77 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 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."