Flexible docking simulations: Scaled collective variable Monte Carlo minimization approach using Bezier splines, and comparison with a standard MonteCarlo algorithm

An algorithm for docking a flexible ligand onto a flexible or rigid recepto r, using the scaled-collective-variables Monte Carlo with energy minimizati on approach, is presented. Energy minimization is shown to be one of the be st techniques for distinguishing between native- and nonnative-generated co nformations. Incorporation of this technique into a Monte Carlo procedure e nables one to distinguish the native conformation directly during the confo rmational search. It avoids the generation of a large number of ligand conf ormers for which more sophisticated energy evaluation tools would have had to be applied to identify the nativelike conformations. The efficiency of t he Monte Carlo minimization was greatly improved by incorporating a new gri d-based energy evaluation technique using Bezier splines for which the ener gy function, as well as all of its derivatives, can be deduced from the val ues at the grid points. Comparison between our ECEPP/3-based algorithm and the Monte Carlo algorithm presented elsewhere (Hart, T. N.; Read, R. J. Pro t Struct Funct Genet 1992, 13, 206-222) has been made for docking NH2-D-Phe -Pro-Arg -COOH, the noncovalent analog of NH2-D-Phe-Pro-Arg- chloromethylke tone (PPACK) onto the active site of human alpha-thrombin. (C) 1999 John Wi ley & Sons, Inc.