Biophysics and Structure to Counter Threats and Challenges
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System-Specific Scoring Functions: Application to Guanine-Containing Ligands and Thrombin Ivan V. Ozerov, Elisabeth D. Balitskaya, and Roman G. Efremov
Abstract Molecular docking is one of the most common and popular computational methods in structural biology. It is widely used for investigations of molecular details of protein functioning and in drug design. Nevertheless, modern docking algorithms are still far from perfection. Development of scoring functions aimed at prediction of spatial structure and free energy of binding for molecular complexes remains a challenging task. With increasing amount of structural data, creation of precise system-specific scoring functions becomes possible. This article describes the physical phenomena underlying efficiency of such scoring functions and demonstrates the related quantitative approaches by the examples of guaninecontaining ligands and thrombin.
2.1 Introduction Molecular docking is a method of molecular modeling aimed at prediction of the spatial structure of a protein-ligand complex and the free energy of ligand binding. Docking procedure can be divided into two separate but interconnected parts: conformational search and scoring function. The conformational search algorithm starts from a random orientation of two molecules and leads to final 3D structure of the biomolecular complex through a
I.V. Ozerov () • E.D. Balitskaya • R.G. Efremov Laboratory of Biomolecular Modeling, Russian Academy of Sciences, M.M. Shemyakin & Yu.A. Ovchinnikov Institute of Bioorganic Chemistry, Ul. Miklukho-Maklaya, 16/10, 117997 GSP, Moscow V-437, Russia I.V. Ozerov • E.D. Balitskaya Department of Bioengineering, M.V. Lomonosov Moscow State University, Biological faculty, Leninskie Gori, 1/73, 119991 GSP-1, Moscow, Russia e-mail: [email protected] J.D. Puglisi and M.V. Margaris (eds.), Biophysics and Structure to Counter Threats and Challenges, NATO Science for Peace and Security Series B: Physics and Biophysics, DOI 10.1007/978-94-007-4923-8 2, © Springer ScienceCBusiness Media Dordrecht 2013
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sequence of stepwise conformational changes. Generally, these are internal rotations around chemical bonds in molecules and translation/rotation of a rather small molecule (ligand) around another larger one (receptor) as a rigid body. In some cases, receptor flexibility is very important and so there are several methods to take it into account. Detailed information about the conformational protein flexibility problem one can find in reviews [1, 2]. Scoring function is used to score (or rank) various putative ligand conformations placed in the receptor binding site at each step of the conformational search procedure according to some predefined criteria. Sometimes, scoring functions are used to predict the free energy of binding. There are three types of scoring functions: forcefield based, stochastic and empirical [3]. Empirical functions are the most commonly used. They represent a natural choice when a proper training set could be constructed. Such scoring funct
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