We introduce a quantum mechanical polarizable force field (QMPFF) fitted solely to QM data at the MP2͞aTZ(-hp) level. Atomic charge density is modeled by point-charge nuclei and floating exponentially shaped electron clouds. The functional form of interaction energy parallels quantum mechanics by including electrostatic, exchange, induction, and dispersion terms. Separate fitting of each term to the counterpart calculated from high-quality QM data ensures high transferability of QMPFF parameters to different molecular environments, as well as accurate fit to a broad range of experimental data in both gas and liquid phases. QMPFF, which is much more efficient than ab initio QM, is optimized for the accurate simulation of biomolecular systems and the design of drugs.drug design ͉ quantum mechanics A ccurate simulation of intermolecular interactions is essential in computational studies of chemical and biological systems ranging from multimer spectroscopy in molecular beams, atomsurface interactions, and catalyzed chemical reactions to protein folding and rational drug design. The most reliable and consistent means for such simulations would be to directly use quantum mechanics. However, this is much too computationally demanding, mandating instead the use of a force field, in which the molecular potential surface is approximated by simple analytical formulas. Commonly used force fields including CHARMM, OPLS-AA, MMFF, and AMBER (1-4) originated with Lifson's and Warshel's (5) consistent force field; they all use two basic types of interactions, bonded and nonbonded. The bonded terms are usually modeled formally as functions of stretching, bending, and torsion, whereas the nonbonded components are more physically grounded and involve electrostatic and van der Waals potentials. Electrostatics is described in terms of fixed point charges, and the van der Waals interaction is usually approximated by the classical Leonard-Jones ''12-6'' potential or its modifications. Empirical parameters that shape the various functional forms are found by fitting to low-level quantum mechanical (QM) and͞or experimental data for simple molecules and their interactions in the solid and liquid phases.Although such force fields have been quite successful in modeling a wide variety of molecular systems, there are significant problems in simulation of liquid-phase solutes (6). These force fields have many possible defects including oversimplified treatment of bonded interactions and approximation of charge distributions by point charges with consequent neglect of charge penetration effects, nonadiabatic motions, and other QM features of intra-and intermolecular interactions. However, the most serious defect is recognized to be the failure to incorporate electronic polarization at a fundamental level, which is especially important in a polar medium such as water. To allow for the effects of polarization, the standard nonpolarizable force fields fit the mean field of the liquid by artificially increased dipole moments, deformed molecular geo...

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We have recently introduced a quantum mechanical polarizable force field (QMPFF) fitted solely to high-level quantum mechanical data for simulations of biomolecular systems. Here, we present an improved form of the force field, QMPFF2, and apply it to simulations of liquid water. The results of the simulations show excellent agreement with a variety of experimental thermodynamic and structural data, as good or better than that provided by specialized water potentials. In particular, QMPFF2 is the only ab initio force field to accurately reproduce the anomalous temperature dependence of water density to our knowledge. The ability of the same force field to successfully simulate the properties of both organic molecules and water suggests it will be useful for simulations of proteins and protein-ligand interactions in the aqueous environment.G eneral-purpose force fields, from Levitt's early protein potential (1) to modern models such as CHARMM, OPLS-AA, MMFF, and AMBER (2-5), which approximate molecular potentials by simple analytical formulas, are in wide use for computational studies of biological systems ranging from the simplest molecular clusters to large complexes involving proteins. In the latter case, the investigations encounter serious computational problems, primarily related to proper conformational sampling and adequate treatment of the long-range intermolecular interactions; however, with advancements in simulation methodologies and the increase in computer speed these difficulties are alleviated so the accuracy of the underlying models becomes the dominant factor.Protein and protein-ligand interactions usually take place in an aqueous environment, which contributes critically to their energetics, e.g., by hydrogen bonding and the hydrophobic effect. Hence, a force field should accurately reproduce the properties of both organic compounds and water if it is to be used for precise calculations of protein-ligand binding, as required for example in drug-design applications. Moreover, the quality of the applications of a force field to water can be considered as a criterion for the accuracy of the approach as a whole. Hence, it is disconcerting that no general-purpose force field has previously succeeded in accurately describing key properties of liquid water.On the other hand, impressive progress has been made in theoretical studies using specialized water potentials. Many of these potentials are empirical, i.e., they have been fitted to experimental data on the thermodynamics and kinetics of liquid water and in some cases ice. The most advanced of these models, such as the pairwise additive TIP5P (6) and polarizable (7-9) potentials, generally provide an accurate description of the most important properties of water and͞or ice. However, no one model is yet able to reproduce in detail the diversity of thermodynamic and kinetic experimental data on both gas and condensed phases under a range of conditions. Moreover, these empirical water potentials cannot be transferred to more general molecular systems ...

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An explicitly polarizable force field based exclusively on quantum data is applied to calculations of relative binding affinities of ligands to proteins. Five ligands, differing by replacement of an atom or functional group, in complexes with three serine proteases-trypsin, thrombin, and urokinase-type plasminogen activator-with available experimental binding data are used as test systems. A special protocol of thermodynamic integration was developed and used to provide sufficiently low levels of systematic error along with high numerical efficiency and statistical stability. The calculated results are in excellent quantitative (rmsd ‫؍‬ 1.0 kcal/mol) and qualitative (R 2 ‫؍‬ 0.90) agreement with experimental data. The potential of the methodology to explain the observed differences in the ligand affinities is also demonstrated. molecular dynamics simulation ͉ serine protease ͉ drug design T he ability to accurately calculate the binding affinity, or equivalently binding free energy, of a ligand for a protein would be highly useful in the field of drug design for lead selection and optimization. Although screening and docking methods (1, 2) have been successful in filtering large chemical databases, they cannot provide definitive calculations of binding energy because of the simplified scoring functions used and the restricted number of states tested. Hence, more accurate calculations have generally been based on molecular mechanics models (3, 4). In these methods the required properties of statistical ensembles are determined by molecular dynamical or Monte Carlo simulations of systems by using a physically grounded description of interactions between particles. The theoretical thermodynamic foundation of such methods is clear, simple, and well established (5).Despite these advantages, as well as initial optimism and long development, only a limited number of successful simulations have been published during the past decade (e.g., refs. 6-14; for review of early results, see refs. 3 and 4). In part, this is explained by many methodological difficulties that must be overcome, especially in accurate and efficient description of long-range interactions and adequate sampling of the conformational space. Major efforts devoted to solving these problems have resulted both in partial success (15, 16) and the recognition of some principal limitations. Notably, several theoretically based techniques have been developed, such as umbrella sampling, the concept of potential of mean force, and artificial restraining potentials, which restrict or decompose the conformational space and simplify adequate sampling (e.g., 11, 17-20).The other principal problem has been the quality of the model potentials or force fields (FFs) used to describe atom-atom interactions. The most questionable point in this respect is the role of nonadditive effects, particularly electronic polarizability. Widely used FFs such as MMFF (21), AMBER (22), OPLS (23), CHARMM (24), and GROMOS (25) are not explicitly polarizable but rather include polarizabil...