ASSESSING ENERGY FUNCTIONS FOR FLEXIBLE DOCKING

A good docking algorithm requires an energy function that is selective , in that it clearly differentiates correctly docked structures from m isdocked ones, and that is efficient, meaning that a correctly docked structure can be identified quickly. We assess the selectivity and eff iciency of a broad spectrum of energy functions, derived from systemat ic modifications of the CHARMM param19/toph19 energy function, in part icular, we examine the effects of the dielectric constant, the solvati on model, the scaling of surface charges, reduction of van der Waals r epulsion, and nonbonded cutoffs. Based on an assessment of the energy functions for the docking of five different Ligand-receptor complexes, we find that selective energy functions include a variety of distance -dependent dielectric models together with truncation of the nonbonded interactions at 8 Angstrom. We evaluate the docking efficiency, the m ean number of docked structures per unit of time, of the more selectiv e energy functions, using a simulated annealing molecular dynamics pro tocol. The largest improvements in efficiency come from a reduction of van der Waals repulsion and a reduction of surface charges. We note t hat the most selective potential is quite inefficient, although a hier archical approach can be employed to take advantage of both selective and efficient energy functions. (C) 1998 John Wiley & Sons, Inc.