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

Jarosaw Pillardy^*, Cezary Czaplewski^*,, Adam Liwo^*,, Jooyoung Lee^*,, Daniel R. Ripoll^§, Rajmund Kamierkiewicz^*,, Stanisaw Odziej, William J. Wedemeyer^*, Kenneth D. Gibson^*, Yelena A. Arnautova^*, Jeff Saunders^*, Yuan-Jie Ye^*, and Harold A. Scheraga^*,¶

^* Baker Laboratory of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853-1301;  Faculty of Chemistry, University of Gdask, Sobieskiego 18, 80-952 Gdask, Poland; and ^§ Cornell Theory Center, Ithaca, NY 14853-3801

Contributed by Harold A. Scheraga, December 22, 2000

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