A FAST AND EFFICIENT PROGRAM FOR MODELING PROTEIN LOOPS

We developed an efficient Monte Carlo Simulated Annealing (MCSA) progr am for modeling protein loops with high speed. The total conformationa l energy in each step of MCSA simulation consists of two parts: the no nbonded atomic interaction represented by a simple soft-sphere potenti al and the harmonic distance constraint to ensure the smooth connectio n of the loop segment to the rest of the protein structure. The soft-s phere potential was a simplified potential that has been successfully used by the authors in modeling the carbohydrate part of glycoprotein systems [H. Zhang, Y. Yang, L. Lai, and Y. Tang(1996), Carbohydrate Re search, Vol. 284, pp, 25-34], It only considers the purely repulsive s teric interactions to avoid artificial attractive forces between atoms in the absence of solvent molecules. The N-terminal of the loop segme nt was connected to the bulk protein part, and two dummy main-chain at oms N and C alpha immediately following the C-terminal of the loop seg ment were constrained to their real positions in the protein structure , which not only assures the correct geometry of loop-protein connecti on but also is more rigorous than the previous work. To improve the sp eed, two strategies, the local region method and grid-mapping method, were devised to accelerate the computation of environmental interactio n that is responsible for the major part of the computing consumption. The grid-mapping method can reduce computational time dramatically. C onformations with rational steric packing and smooth connection to the rest of the protein structure were generated by the MCSA program, and then were refined by the empirical force field CHARMm [B. R. Brook, R . E. Braccoleri, B. D. Olafson, D. J. States, S. Swaminathan, and M. K arplus (1983), Journal of Computational Chemistry, Vol. 4, pp. 187-217 ]. Bovine pancreatic trypsin inhibitor (BPTI) was used as an example t o test the ability of loop modeling of the method, and five loops in B PTI were calculated. Conformations close to the crystal structure were generated for all of them. With the criteria of CHARMm energy, near-n ative conformations can be selected, for example, the backbone rms dev iation 0.93 Angstrom from the crystal structure was gotten for the lon gest 9-residue loop. (C) 1997 John Wiley & Sons, Inc.