Recent improvements in prediction of protein structure by global optimization of a potential energy function

Recent improvements of a hierarchical ab initio or de novo approach for predicting both alpha and beta structures of proteins are described. The united-residue energy function used in this procedure includes multibody interactions from a cumulant expansion of the free energy of polypeptide chains, with their relative weights determined by Z-score optimization. The critical initial stage of the hierarchical procedure involves a search of conformational space by the conformational space annealing (CSA) method, followed by optimization of an all-atom model. The procedure was assessed in a recent blind test of protein structure prediction (CASP4). The resulting lowest-energy structures of the target proteins (ranging in size from 70 to 244 residues) agreed with the experimental structures in many respects. The entire experimental structure of a cyclic alpha -helical protein of 70 residues was predicted to within 4.3 Angstrom alpha -carbon (C-alpha) rms deviation (rmsd) whereas, for other alpha -helical proteins, fragments of roughly 60 residues were predicted to within 6.0 Angstrom C-alpha rmsd. Whereas beta structures can now be predicted with the new procedure, the success rate for alpha/beta- and beta -proteins is lower than that for alpha -proteins at present. For the beta portions of alpha/beta structures, the C-alpha rmsd's are less than 6.0 Angstrom for contiguous fragments of 30-40 residues; for one target, three fragments (of length 10, 23, and 28 residues, respectively) formed a compact part of the tertiary structure with a C-alpha rmsd less than 6.0 Angstrom. Overall, these results constitute an important step toward the ab initio prediction of protein structure solely from the amino acid sequence.