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 assemble native-like structures from fragments of unrelated protein struc-tures with similar local sequences using Bayesian scoring functions. En-vironment and residue pair speci®c contributions to the scoring functions appear as the ®rst two terms in a series expansion for the residue prob-ability distributions in the protein database; the decoupling of the dis-tance and environment dependencies of the distributions resolves the major problems with current database-derived scoring functions noted by Thomas and Dill. The simulated annealing procedure rapidly and fre-quently generates native-like structures for small helical proteins and bet-ter than random structures for small b sheet containing proteins. Most of the simulated structures have native-like solvent accessibility and second-ary 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 sequence information and different types of conformational constraints on the overall performance of the method, and the ability of a variety of recently developed scoring func-tions to recognize the native-like conformations in the ensembles of simu-lated structures