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

<jats:p> Recent improvements of a hierarchical <jats:italic>ab initio</jats:italic> or <jats:italic>de novo</jats:italic> approach for predicting both α and β 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 α-helical protein of 70 residues was predicted to within 4.3 Å α-carbon (C <jats:sup>α</jats:sup> ) rms deviation (rmsd) whereas, for other α-helical proteins, fragments of roughly 60 residues were predicted to within 6.0 Å C <jats:sup>α</jats:sup> rmsd. Whereas β structures can now be predicted with the new procedure, the success rate for α/β- and β-proteins is lower than that for α-proteins at present. For the β portions of α/β structures, the C <jats:sup>α</jats:sup> rmsd's are less than 6.0 Å 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 <jats:sup>α</jats:sup> rmsd less than 6.0 Å. Overall, these results constitute an important step toward the <jats:italic>ab initio</jats:italic> prediction of protein structure <jats:italic>solely</jats:italic> from the amino acid sequence. </jats:p>