Ab initio protein structure prediction of CASP III targets using ROSETTA

To generate structures consistent with both the local and nonlocal interact ions responsible for protein stability, 3 and 9 residue fragments of known structures with local sequences similar to the target sequence were assembl ed into complete tertiary structures using a Monte Carlo simulated annealin g procedure (Simons et al,, J Mol Biol 1997; 268:209-225), The scoring func tion used in the simulated annealing procedure consists of sequence-depende nt terms representing hydrophobic burial and specific pair interactions suc h as electrostatics and disulfide bonding and sequence-independent terms re presenting hard sphere packing, alpha-helix and beta-strand packing, and th e collection of beta-strands in beta-sheets (Simons et al,, Proteins 1999;3 4:82-95), For each of 21 small, ab initio targets, 1,200 final structures m ere constructed, each the result of 100,000 attempted fragment substitution s. The five structures submitted for the GASP III experiment mere chosen fr om the approximately 25 structures with the lowest scores in the broadest m inima (assessed through the number of structural neighbors; Shortie et al,, Proc Natl Acad Sci USA 1998;95:1158-1162). The results were encouraging: h ighlights of the predictions include a 99-residue segment for MarA with an rmsd of 6.4 Angstrom to the native structure, a 95-residue (full length) pr ediction for the EH2 domain of EPS15 with an rmsd of 6.0 Angstrom, a 75-res idue segment of DNAB helicase with an rmsd of 4.7 Angstrom, and a 67-residu e segment of ribosomal protein L30 with an rmsd of 3.8 Angstrom. These resu lts suggest that ab initio methods may soon become useful for low-resolutio n structure prediction for proteins that lack a close homologue of known st ructure. (C) 1999 Wiley-Liss, Inc.