Physics-based protein-structure prediction using a hierarchical protocol based on the UNRES force field: Assessment in two blind tests.

Recent improvements in the protein-structure prediction method developed in our laboratory, based on the thermodynamic hypothesis, are described. The confrontational space is searched extensively at the united-residue level by using our physics-based UNRES energy function and the confrontational space annealing method of global optimization. The lowest-energy coarse-grained structures are then converted to an all-atom representation and energy- minimized with the ECEPP/3 force field. The procedure was as- sensed in two recent blind tests of protein-structure prediction. During the first blind test we predicted large fragments of a and a+fl proteins 160-70 residues with Crams deviation (rmsd) <6 Al. However, for a-f-fl proteins, significant topological errors occurred despite low rmsd values. In the second exercise, we predicted whole structures of five proteins (two a and three a+fl, with sizes of 53-235 residues) with remarkably good accuracy. In particular, for the genomic target TM0487 (a 102-residue a+fl protein from Therrnotoga maritima), we predicted the complete, topologically correct structure with 7.3-A Ca rmsd. So far this protein is the largest a+fl protein predicted based solely on the amino acid sequence and a physics-based potential-energy function and search procedure. For target T0198, a phosphate transport system regulator PhoU from 11 maritima (a 235-residue mainly a-helical protein), we predicted the topology of the whole six-helix bundle correctly within 8 A rmsd, except the 32 C-terminal residues, most of which form a p-hairpin. These and other examples described in this work demonstrate significant progress in physics-based protein-structure prediction. [ABSTRACT FROM AUTHOR]