computer modeling in molecular biology.pdf

32 Tim J I? Hubbard and Arthur M. LeskNote Added in ProofThere is a serious ‘catch 22’ like problem in evaluating the effectiveness of proteinmodelling: if you model a structure that is known, you cannot be sure how biasedyou were by that prior knowledge (since almost no modelling system is entirely ablack box) whereas if you model a structure that is unknown you cannot assess theaccuracy of your models. One way around this is to build models ‘just in time’, i. e.immediately before publication of an experimentally-determined structure, so it ispossible to evaluate the accuracy of your model with the confidence that it was ablind prediction. When this chapter was written there had been isolated examples ofthis sort of arrangement between theoreticians and experimentalists but they werequite rare.In the last month there has been a meeting to evaluate the first ever large scaleprotein structure prediction competition, which ran for most of 1994 [94]. -35groups made - 150 predictions about - 25 target proteins. The predictions were consideredin three categories : homology modelling, fold recognition and ab initioprediction. The results were instructive:Homology modelling naturally gives the most reliable predictions, but despite theefforts made to automate the modelling process, it is clear that where the templatestructure used to build the model differs substantially from the experimental structurethe model is generally wrong: we are unable to model the variations that commonlyoccur between homologous proteins (loops, man chain shift and the associateddifferent side chain packing) with much greater accuracy than was possible byhand 10-15 years ago.Although the accuracy of homology modelling was disappointing, the number oftargets that could potentially be modelled based on a template structure is going toincrease, since the meeting demonstrated that fold recognition techniques (using newmethods such as ‘threading’) can already indentify the most similar fold in the structuredatabase in a substantial number of cases. Threading is still a very young techniqueand it is clear that many improvements can be made, so the accuracy and sensitivitycan only increase.Finally, it does appear that useful ab initio structure predictions can be made fortargets where there are many homologous sequences. Secondary structure predictionby the PHD method [13, 141 in such cases is sufficiently reliable for predictors to considerhow these secondary structural elements might be assembled (i. e. to attempta full tertiary prediction) and new techniques are emerging to predict such long rangeinteractions based on specialized potentials [95] and correlation information 1961.