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

S. Odziej ^*, , C. Czaplewski ^*, , A. Liwo ^*, , M. Chinchio ^*, M. Nanias ^*, J. A. Vila ^*, , M. Khalili ^*, Y. A. Arnautova ^*, A. Jagielska ^*, M. Makowski ^*, , H. D. Schafroth ^*, R. Kamierkiewicz ^*, , D. R. Ripoll ^*, , J. Pillardy ^*, , J. A. Saunders ^*, Y. K. Kang ^*, ¶, K. D. Gibson ^* and H. A. Scheraga ^*, ||

^*Baker Laboratory of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853-1301; Faculty of Chemistry, University of Gdask, Sobieskiego Str. 18, 80-952 Gdask, Poland; Instituto de Matemática Aplicada San Luis, Consejo Nacional de Investigaciones Científicas y Técnicas de Argentina, Facultad de Ciencias Físico Matemáticas y Naturales, Universidad Nacional de San Luis, Ejército de los Andes 950, 5700 San Luis, Argentina; Cornell Theory Center, Cornell University, Ithaca, NY 14853-3801; and ^¶Department of Chemistry, Chungbuk National University, Cheongju, Chungbuk 361-763, Korea

Contributed by H. A. Scheraga, March 31, 2005

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 and + proteins [60–70 residues with C rms deviation (rmsd) <6 Å]. However, for + proteins, significant topological errors occurred despite low rmsd values. In the second exercise, we predicted whole structures of five proteins (two and three +, with sizes of 53–235 residues) with remarkably good accuracy. In particular, for the genomic target TM0487 (a 102-residue + protein from Thermotoga maritima), we predicted the complete, topologically correct structure with 7.3-Å C rmsd. So far this protein is the largest + 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 -helical protein), we predicted the topology of the whole six-helix bundle correctly within 8 Å rmsd, except the 32 C-terminal residues, most of which form a -hairpin. These and other examples described in this work demonstrate significant progress in physics-based protein-structure prediction.