OPLS3: A Force Field Providing Broad Coverage of Drug-like Small Molecules and Proteins.

The parametrization and validation of the OPLS3 force field for small molecules and proteins are reported. Enhancements with respect to the previous version (OPLS2.1) include the addition of off-atom charge sites to represent halogen bonding and aryl nitrogen lone pairs as well as a complete refit of peptide dihedral parameters to better model the native structure of proteins. To adequately cover medicinal chemical space, OPLS3 employs over an order of magnitude more reference data and associated parameter types relative to other commonly used small molecule force fields (e.g., MMFF and OPLS_2005). As a consequence, OPLS3 achieves a high level of accuracy across performance benchmarks that assess small molecule conformational propensities and solvation. The newly fitted peptide dihedrals lead to significant improvements in the representation of secondary structure elements in simulated peptides and native structure stability over a number of proteins. Together, the improvements made to both the small molecule and protein force field lead to a high level of accuracy in predicting protein-ligand binding measured over a wide range of targets and ligands (less than 1 kcal/mol RMS error) representing a 30% improvement over earlier variants of the OPLS force field.

Integrated Modeling Program, Applied Chemical Theory (IMPACT).

We provide an overview of the IMPACT molecular mechanics program with an emphasis on recent developments and a description of its current functionality. With respect to core molecular mechanics technologies we include a status report for the fixed charge and polarizable force fields that can be used with the program and illustrate how the force fields, when used together with new atom typing and parameter assignment modules, have greatly expanded the coverage of organic compounds and medicinally relevant ligands. As we discuss in this review, explicit solvent simulations have been used to guide our design of implicit solvent models based on the generalized Born framework and a novel nonpolar estimator that have recently been incorporated into the program. With IMPACT it is possible to use several different advanced conformational sampling algorithms based on combining features of molecular dynamics and Monte Carlo simulations. The program includes two specialized molecular mechanics modules: Glide, a high-throughput docking program, and QSite, a mixed quantum mechanics/molecular mechanics module. These modules employ the IMPACT infrastructure as a starting point for the construction of the protein model and assignment of molecular mechanics parameters, but have then been developed to meet specialized objectives with respect to sampling and the energy function.

Pseudospectral Local Second-Order Møller-Plesset Methods for Computation of Hydrogen Bonding Energies of Molecular Pairs.

We present a methodology for computing the binding energy of molecular dimers based on extrapolation of pseudospectral local second-order Moller-Plesset (MP2), or PS-LMP2, energies to the basis set limit. The extrapolation protocol is based on carrying out PS-LMP2 calculations with the Dunning cc-pVTZ (-f) and cc-pVQZ (-g) basis sets and then using a simple two-parameter function to compute the final basis set limit results. The function is parametrized to ultralarge basis set MP2 calculations for 5 molecular pairs taken from the literature and then tested by calculating results for a set of formamide dimers for which such calculations have also been carried out. The results agree to within ca. 0.2 kcal/mol with the conventional MP2 large basis set calculations. A specialized, but relatively simple, protocol is described for eliminating noise due to overcompleteness of the basis set. Timing results are presented for the LMP2 calculations, and comparisons are made with the LMP2 methodology of the QChem program. CPU time required by each of the methods scales as N(3), where N is the number of the basis functions, with the PS-LMP2 approach displaying a 2- to 3-fold advantage in the prefactor. We also discuss one set of test cases for which the PS-LMP2 results disagree with those obtained from an alternative type of MP2 calculation, N-methyl acetamide (NMA) dimers, and show that the results for liquid-state simulations using polarizable parameters derived by fitting to the PS-LMP2 binding energies appear to produce better results when compared with experimental data. The convergence issues associated with the alternative MP2 formulation remain to be investigated.

A Polarizable Force Field and Continuum Solvation Methodology for Modeling of Protein-Ligand Interactions.

A polarizable force field, and associated continuum solvation model, have been developed for the explicit purpose of computing and studying the energetics and structural features of protein binding to the wide range of ligands with potential for medicinal applications. Parameters for the polarizable force field (PFF) are derived from gas-phase ab initio calculations and then utilized for applications in which the protein binding to ligands occurs in aqueous solvents, wherein the charge distributions of proteins and ligands can be dramatically altered. The continuum solvation model is based on a self-consistent reaction field description of solvation, incorporating an analytical gradient, that allows energy minimizations (and, potentially, molecular dynamics simulations) of protein/ligand systems in continuum solvent. This technology includes a nonpolar model describing the cost of cavity formation, and van der Waals interactions, between the continuum solvent and protein/ligand solutes. Tests of the structural accuracy and computational stability of the methodology, and timings for energy minimizations of proteins and protein/ligand systems in the condensed phase, are reported. In addition, the derivation of polarizability, electrostatic, exchange repulsion, and torsion parameters from ab initio data is described, along with the use of experimental solvation energies for determining parameters for the solvation model.

Derivation of class II force fields. VIII. Derivation of a general quantum mechanical force field for organic compounds.

A class II valence force field covering a broad range of organic molecules has been derived employing ab initio quantum mechanical "observables." The procedure includes selecting representative molecules and molecular structures, and systematically sampling their energy surfaces as described by energies and energy first and second derivatives with respect to molecular deformations. In this article the procedure for fitting the force field parameters to these energies and energy derivatives is briefly reviewed. The application of the methodology to the derivation of a class II quantum mechanical force field (QMFF) for 32 organic functional groups is then described. A training set of 400 molecules spanning the 32 functional groups was used to parameterize the force field. The molecular families comprising the functional groups and, within each family, the torsional angles used to sample different conformers, are described. The number of stationary points (equilibria and transition states) for these molecules is given for each functional group. This set contains 1324 stationary structures, with 718 minimum energy structures and 606 transition states. The quality of the fit to the quantum data is gauged based on the deviations between the ab initio and force field energies and energy derivatives. The accuracy with which the QMFF reproduces the ab initio molecular bond lengths, bond angles, torsional angles, vibrational frequencies, and conformational energies is then given for each functional group. Consistently good accuracy is found for these computed properties for the various types of molecules. This demonstrates that the methodology is broadly applicable for the derivation of force field parameters across widely differing types of molecular structures. Copyright 2001 John Wiley & Sons, Inc. J Comput Chem 22: 1782-1800, 2001