Towards an automatic method of predicting protein stucture by homology: an evaluation of suboptimal sequence alignments

A major problem in predicting protein structure by homologymodelling is that the sequence alignment from which the modelis built may not be the best one in terms of the correct equivalencingof residues assessed by structural or functional criteria. Auseful strategy is to generate and examine a number of suboptimalalignments as better alignments can often be found away fromthe optimal. A procedure to filter rapidly suboptimal alignmentsbased on measurement of core volumes and packing pair potentialsis investigated. The approach is benchmarked on three pairsof sequences which are non-trivial to align correctly, namelytwo immunoglobulin domains, plastocyanin with azurin and twodistant globin sequences. It is shown to be useful to reducea large ensemble of possible alignments down to a few whichcorrespond more closely to the correct (structure based) alignment.