Progress in Force-Field Calculations of Molecular Interaction Fields and Intermolecular Interactions

Abstract

The first four terms in Eq. 1 describe the energies due to deviations of structural features and non-bonded distances from their ‘ideal’ or reference values, Eelectrostatic is the energy contribution due to attraction or repulsion between charges (or dipoles) and some forcefields use a special hydrogen-bonding term, Ehydrogen Bond. Additional terms are required — e.g. for calculations of vibrational frequences and thermodynamic quantities. Force-field calculations [l–3] are used in many research areas aiming at an understanding, modelling and subsequent exploiting of structure-activity/property relationships. Such areas include conformational analysis, pharmacophore identification, ligand docking to macromolecules, de novo ligand design, comparative molecular field analysis (CoMFA) and identification of favorable binding sites from molecular interaction fields. Although ab initio quantum chemical computational methodology [4] today is competitive with experiments in determining a large number of molecular properties, force-fields are commonly used due to the prohibitive amounts of computer time required for high-level ab initio calculations on series of drug-sized molecules and on large molecular systems as those involved in ligand-protein interactions. For calculations of, for example, molecular structures and conformational energies force-field calculations may give results in excellent agreement with experiments, provided that the force-field parameters involved in the calculations have been accurately determined [1,5]. The force-fields used for calculations of molecular interaction fields and intermolecular interactions vary from very simple force-fields as those commonly used in CoMFA 3D QSAR studies [6] to the more sophisticated force-field used for the calculation of molecular interaction fields by the GRID method [3,7-1 l], and the complex force-fields required for calculations of complexation energies and geometries of general intermolecular interactions between complete molecules [2]. The aim of this chapter is to review and discuss some recent developments and evaluations of force-fields used for the calculations of molecular interaction fields and intermolecular energies and geometries. The review is not meant to be exhaustive, but some