Comparison of stochastic optimization methods for receptor–ligand docking H. Merlitz, W. Wenzel * Forschungszentrum Karlsruhe GmbH, Institut f€ ur Nanotechnologie, Postfach 3640, D-76021 Karlsruhe, Germany Received 20 April 2002; in final form 17 June 2002 Abstract We compare the efficiency of three stochastic optimization methods, simulated annealing, parallel tempering and stochastic tunneling to locate the global minima of complex and rugged potential energy surfaces arising from atomistic models for receptor–ligand docking. The stochastic tunneling method proves to be the most efficient generic approach for atomistic receptor–ligand docking in the rigid ligand – rigid receptor approximation. Ó 2002 Elsevier Science B.V. All rights reserved. 1. Introduction The development of methods to efficiently de- termine the global minima of complex and rugged energy landscapes remains a challenging problem with applications in many scientific and techno- logical areas. In particular for NP-hard [1,2] problems, straightforward enumerative as well as sophisti- cated branch-and-bound techniques become pro- hibitively expensive and stochastic methods offer the only acceptable compromise between the computational cost of the method and its reli- ability. In such techniques the global minimization is accomplished by the simulation of a fictitious dynamical process for a ‘particle’ on the multi-di- mensional potential energy surface (PES). This particle explores the potential energy surface in a biased random walk that is designed to guide it to low-energy regions. In one of the most widely used methods, the simulated annealing technique (SA) [3], the PES is explored in a Monte–Carlo simulation with grad- ually decreasing temperature. The final tempera- ture is chosen small enough to constrain the dynamics of the particle to the immediate vicinity of the nearest local minimum of the PES, while the largest temperature must be sufficiently high to allow an essentially random search of the PES. On rugged PES this strategy routinely fails, because transition states between adjacent local minima are too high to be overcome at temperatures suffi- ciently small to resolve the energy differences be- tween them. Here we investigate a family of methods that have sought to address this generic deficiency of SA by allowing the dynamical process to pass through thermodynamically inaccessible regions of 19 August 2002 Chemical Physics Letters 362 (2002) 271–277 www.elsevier.com/locate/cplett * Corresponding author. Fax: +72-47-82-6434. E-mail address: wenzel@int.fzk.de (W. Wenzel). 0009-2614/02/$ - see front matter Ó 2002 Elsevier Science B.V. All rights reserved. PII:S0009-2614(02)01035-7