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

Abstract

Recent improvements in the protein-structure prediction method developed in our laboratory, based on the thermodynamic hypothesis, are described. The conformational space is searched extensively at the united-residue level by using our physics-based UNRES energy function and the conformational 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 assessed in two recent blind tests of protein-structure prediction. During the first blind test, we predicted large fragments of alpha and alpha+beta proteins [60-70 residues with C(alpha) rms deviation (rmsd) <6 A]. However, for alpha+beta proteins, significant topological errors occurred despite low rmsd values. In the second exercise, we predicted whole structures of five proteins (two alpha and three alpha+beta, with sizes of 53-235 residues) with remarkably good accuracy. In particular, for the genomic target TM0487 (a 102-residue alpha+beta protein from Thermotoga maritima), we predicted the complete, topologically correct structure with 7.3-A C(alpha) rmsd. So far this protein is the largest alpha+beta 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 T. maritima (a 235-residue mainly alpha-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 beta-hairpin. These and other examples described in this work demonstrate significant progress in physics-based protein-structure prediction.

Fig. 1.

The best predicted structures of CASP5 targets T0149_2 (the C-terminal domain of T0149) (A) and T0129 (B) and CASP6 targets T0215 (C), T0281 (D), T0223_2 (the second domain of T0223) (E), T0230 (F), and T0198 (G). The correctly predicted parts of the structure are marked as cylinders (for α-helices), ribbons (for β-strands), and thick lines (loops and other unstructured regions), and the incorrectly predicted parts are shown as thin lines. The chains are colored from blue to red from the N to the C terminus.