ASSEMBLY OF PROTEIN TERTIARY STRUCTURES FROM FRAGMENTS WITH SIMILAR LOCAL SEQUENCES USING SIMULATED ANNEALING AND BAYESIAN SCORING FUNCTIONS

We explore the ability of a simple simulated annealing procedure to as semble native-like structures from fragments of unrelated protein stru ctures with similar local sequences using Bayesian scoring functions. Environment and residue pair specific contributions to the scoring fun ctions appear as the first two terms in a series expansion for the res idue probability distributions in the protein database; the decoupling of the distance and environment dependencies of the distributions res olves the major problems with current database-derived scoring functio ns noted by Thomas and Dill. The simulated annealing procedure rapidly and frequently generates native-like structures for small helical pro teins and better than random structures for small beta sheet containin g proteins. Most of the simulated structures have native-like solvent accessibility and secondary structure patterns, and thus ensembles of these structures provide a particularly challenging set of decoys for evaluating scoring functions. We investigate the effects of multiple s equence information and different types of conformational constraints on the overall performance of the method, and the ability of a variety of recently developed scoring functions to recognize the native-like conformations in the ensembles of simulated structures. (C) 1997 Acade mic Press Limited.