Prediction of protein structure: The problem of fold multiplicity

Abstract

Three-dimensional (3D) models of four CASP3 targets were calculated using a simple modeling procedure that includes prediction of regular secondary structure, analysis of possible Β-sheet topologies, assembly of amphiphilic helices and Β-sheets to bury their nonpolar surfaces, and adjustment of side-chain conformers and loops to provide close packing and saturation of the “hydrogen bond potential” (exposure of all polar groups to water or their involvement in intramolecular hydrogen bonds). It has been found that this approach allows construction of 3D models that, in some cases, properly reproduce the structural class of the protein (such as Β-barrel or Β-sandwich of definite shape and size) and details of tertiary structure (such as pairing of Β-strands), although all four models were more or less incorrect. Remarkably, some models had fewer water-exposed nonpolar side-chains, more hydrogen bonds, and smaller holes than the corresponding native structures (although the models had a larger water-accessible nonpolar surface). The results obtained indicate that hydrophobicity patterns do not unequivocally determine protein folds, and that any ab initio or fold recognition methods that operate with imprecise potential energy functions, or use crude geometrical approximations of the peptide chain, will probably produce many different nonnative structures. Proteins Suppl 1999;3:199–203. © 1999 Wiley-Liss, Inc.