Protein fold refinement: building models from idealized folds using motif constraints and multiple sequence data

A general solution to the problem of directly incorporatingdata from multiple sequence alignments into the constructionof molecular models was approached through the calculation ofan estimated pairwise distance based on conserved hydrophobidty.A scaling method was developed that allowed the required bulkgeometric properties of the estimated pair-wise distances (meanand mean squared) to mimic those expected in a globular protein.These properties were maintained independently of the composition,length, number or degree of conservation of the original sequences.Despite being a poor estimate for individual distances, thescaled distances were found to be compatible with the nativestructure and could be weighted highly. While the estimateddistances provided a general drive towards hydrophobk packing,more specific structures (including secondary structures andmotifs) were induced by regularization towards an ideal form.These constraints were used to refine an outline starting structure(derived only from secondary structure axes) towards a compactform that was sufficiently protein-like for side chains to beadded with almost no further adjustment of the a-carbon positions.This process allows rough folds based on abstract representationsof protein architecture to be rapidly converted to a form wherethey can be analysed by the growing number of methods designedto assess molecular models.