computer modeling in molecular biology.pdf

10 Tim J. I? Hubbard and Arthur M. Lesk2.1 IntroductionThe modelling of protein structures comprises a wide variety of activities, coveringa multitude of sins plus an occasional good deed. Thus, although we shall includediscussion of claims in addition to hard results (else there would be little to writeabout) we emphasise that “what you get is what you see”, not what people tell youthat they get: Any method that has not been subjected to controlled blind tests isof dubious worth.It is useful to start by classifying the types of methods used according to the startinginformation, or “input”; and the expected nature and quality of the results, the“output”. This paper is not intended as a comprehensive review of research on theprotein folding and protein structure prediction problems. Nor is it a step-by-stepguide to constructing a protein model. Instead it is an introduction to a number ofmethods that can be applied now to problems of modelling the structure of a proteinsequence, with the emphasis on allowing the reader who wants to build a model todecide whether his goals are currently practicable. Improvements that can reasonablybe expected in the future are also outlined.2.1.1 The Difficulty of Protein Structure PredictionIt is generally accepted that the amino acid sequences of proteins contain sufficientinformation to specify how the linear chain folds up into a compact 3-D structure.The evidence for this is the type of protein refolding experiments carried out firstby Anfinsen [l] and extended by many workers to other systems. The existence of“chaperone” proteins, which are in some cases necessary for protein folding,modifies but does not overturn the fundamental general principle [2]. It should benoted that the ability of many intact proteins to refold after denaturation proves thattheir folding does not depend on the process of protein synthesis: it cannot be truethat the initially-synthesised N-terminus must serve as a nucleus for folding.We take as our starting point, therefore, that the amino acid sequence of a proteindetermines the conformation. Nature therefore has an “algorithm” for mapping aset of amino acid sequences into three-dimensional structures. There are two possibleapproaches to trying to predict structure from sequence : deductive methods basedon general physico-chemical principles (this is what nature does), and inductive approachesbased on studies of the known protein structures, including modelling byhomology.Since the folding of an extended chain is a dynamic process the most physicallyrealistic approach to the problem is the simulation of the motion of all atoms of aprotein chain (molecular dynamics: MD) [3]. There are a number of currently in-