jones at bsm.biochemistry.ucl.ac.uk (David Jones) writes:
>Rob has made some interesting points regarding the computability of the
>protein folding function. In terms of theoretical protein folding I think
>it is necessary to divide the approaches into two classes: ab initio and
>knowledge-based. Ab initio protein folding simulations attempt to model
>the precise form of the physical forces that are exerted on a protein
>chain during the folding process and effectively minimize these forces
>(generally speaking these days, dynamically). Such simulations offer
>insight into the general nature of the folding process, but the results
>obtained are far from the native conformation of the protein. These
>simulations are hampered by a number of things. Firstly accurate models
>of the forces we think to be important to the protein's conformation are
>computationally expensive - they need to consider side chain positions,
>they need at least the positions of the polar hydrogen atoms and they
>really need a good model of the entropic effects of solvent. Even when
>these forces are simulated to the best of our current ability it is
>clear that these are very poor models of reality indeed.
Your point that the solvent models are bad is well made. The problem is
that some parts of the these so-called 'physical' potential energy functions
are probably very poor models of reality (e.g. solvent). But on the other
hand, some parts are probably quite good. It's the old point about you
overall model being limited by the weakest part, which makes the overall
results so bad. I think progress is being made on working out which bits of
the energy functions are good, and which aren't. When we know that, we
just need to work out ways of getting around the bad (difficult) bits and
we'll he home and dry!
> Considering the
>complexity of average-sized protein domains I would be very surprised if
>a purely ab initio method (i.e. without any knowledge of the intended
>conformation) ever managed to closely approximate the native
>fold of such structures within 20 years, if ever.
It would be an extremely big deal if someone could _really_ predict
the structure of even a small protein ab initio. The smallest protein
that folds by the basic 'rules' of protein folding (i.e. no disulphides
or things to allow people to fudge the results) has only 647 atoms (including
ALL (not just polar) hydrogens), and I think we could at least be optimistic
that it won'y be as long as 20 years before some people would
have the computer power do some 'complicated' calculations on molecules of
this size.
(stuff deleted)
>So what are the future prospects? Well I would expect that within about
>10-15 years or so, somebody, somewhere will have a program that will
>be able to predict the tertiary structure of a given protein sequence
>with at least reasonable accuracy (say to 3-4 A RMSD).
> I expect this program
>will be based on some kind of pattern recognition method - either
>recognizing whole folds or recurrent sub-structures. I am very doubtful,
>however, that the algorithm in use in this futuristic program will have
>anything in common with the "algorithm" proteins actually use.
If these future programs give predicted structures with
about 3-4 Angstrom r.m.s.d. from the correct structure, then that is
going to be a problem for rationalised/predicting function - and certainly
that level of accuracy will be way behind of what the then state-of-the-art
experimental techniques. I think, though, that you may be right in this
estimate of accuracy of these kind of techniques. That's that's why it's
worth trying algorithms that _do_ have something in common with the
'algorithm(s)' that proteins acutally use to fold - they may give better
results in the long (or short!) term.
(stuff deleted)
> If someone works out that
>proteins fold by doing X, Y and then Z but that we cannot hope to
>simulate X or Y let alone Z, is this a solution?
Yes!
_________________________________________________________________________
|| ,_ o Simon M. Brocklehurst,
| / //\, Oxford Centre for Molecular Sciences
| \>> | Department of Biochemistry, University of Oxford,
| \\, Oxford, UK.
| E-mail: s.m.brocklehurst at bioc.cam.ac.uk (reliable)
| or smb at bioch.ox.ac.uk (much less reliable)
|________________________________________________________________________
