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or there's this approach http://www.nature.com/doifinder/10.1038/nsmb0306-184 Nature Structural & Molecular Biology 13, 184 - 185 (2006). J ---------------------- Dr Judith Murray-Rust Structural Biology Lab Cancer Research UK London WC2A 3PX > -----Original Message----- > From: [EMAIL PROTECTED] [mailto:[EMAIL PROTECTED] On > Behalf Of ?????a?? G????? > Sent: 11 January 2007 19:44 > To: ccp4bb@dl.ac.uk > Subject: Re: [ccp4bb]: Modelling disordered side-chains > > *** For details on how to be removed from this list visit the *** > *** CCP4 home page http://www.ccp4.ac.uk *** > > > > Dear All, > > This thread has already grown too much, so I should start by > apologising for > adding yet another long message to your mbox. > > Assume, for the sake of a thought experiment, that instead of the safe > academic environment of my office, I find myself with gun > pointed straight > into my head and a European grant committee (across the room) > demanding from > me to re-determine my latest structure. What they want me to do, is to > produce a new PDB file that will represent in the best > possible way _not_ > just the experimentally determined electron density map, but > everything that > I know about the problem in hand (hint: what have I deposited > ?). Assume, > further, that they explicitly demanded that I only use > computational methods > (no more experiments, sorry). What should I do with those 'missing' > surface-exposed highly mobile side-chains ? I would > definitely not declare > them 'missing' (unless, of course, I knew better based on chemical, > biological or other insight). Similarly, I would not just use the most > highly populated rotamer from a library, mostly because such > a treatment > completely ignores the different environments of the specific > side chains in > the given structure. Because they asked me for a PDB file, > re-inventing a > new structure-description format is not an option. What > should I do (for the > life of me)? Having thought about it for a while [a gun > pointing straight > into ones' head seems to help clarifying ones' thoughts; we > should possibly > try this with doctoral students], I believe that I would have > ended-up doing > molecular dynamics: Take the structure, add all missing > side-chains in a > sensible (but otherwise arbitrary) conformation and do a > couple of long, > state-of-the-art molecular dynamics simulations > (state-of-the-art meaning > with a modern force field, full electrostatics, explicit > waters, etc). The > dynamics of individual side-chains (assuming that the core of > the structure > remains stable) are well-within the time scale of todays' > molecular dynamics > simulations (and you can always confirm convergence via a principal > component analysis). Then, align the missing side-chains on > the backbone and > do a cluster analysis of their MD-derived conformations to > identify the > major conformers. The relative residence times (for each > conformation) would > be deposited as occupancies, the atomic fluctuations would give the > corresponding temperature factors. And I would then have to > hold my breath > waiting to see what the committee thinks about this chimeric > (experimental > plus theoretical) model of mine. > > Again apologies for the rant, > Nicholas > > ps. Hard-core crystallographers ready to dismiss molecular dynamics as > "fantasy, pure-and-simple" will be reminded that a > significant portion of > PDB (ie. NMR structures) is the result of the restrained > application of > molecular dynamics force fields (and that, of course, > molecular dynamics is > indeed fantasy, pure-and-simple ;-). > > -- > > > Dr Nicholas M. Glykos, Department of Molecular > Biology and Genetics, Democritus University of Thrace, > Dimitras 19, 68100 Alexandroupolis, GREECE, Fax ++302551030613 > Tel ++302551030620 (77620), http://www.mbg.duth.gr/~glykos/ > > >
