Edward Harder

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.

Efficient multiple time step method for use with Ewald and particle mesh Ewald for large biomolecular systems

The particle–particle particle–mesh (P3M) method for calculating long-range electrostatic forces in molecular simulations is modified and combined with the reversible reference system propagator algorithm (RESPA) for treating the multiple time scale problems in the molecular dynamics of complex systems with multiple time scales and long-range forces. The resulting particle–particle particle–mesh Ewald RESPA (P3ME/RESPA) method provides a fast and accurate representation of the long-range electrostatic interactions for biomolecular systems such as protein solutions. The method presented here uses a different breakup of the electrostatic forces than was used by other authors when they combined the Particle Mesh Ewald method with RESPA. The usual breakup is inefficient because it treats the reciprocal space forces in an outer loop even though they contain a part that changes rapidly in time. This does not allow use of a large time step for the outer loop. Here, we capture the short-range contributions in the...

Understanding the dielectric properties of liquid amides from a polarizable force field.

The role played by electronic polarization in the dielectric properties of liquid N-methyl acetamide (NMA) is examined using molecular dynamics simulations with a polarizable force field based on classical Drude oscillators. The model presented is the first force field shown to reproduce the anomalously large dielectric constant of liquid NMA. Details of the molecular polarizability are found to be important. For instance, all elements of the polarizability tensor, rather then just the trace, impact on the condensed phase properties. Two factors related to electronic polarizability are found to contribute to this large dielectric constant. First is the significant enhancement of the mean amide molecular dipole magnitude, which is 50% larger in the liquid than in the gas phase. Second is the consequent strong hydrogen bonding between molecular neighbors that enhances the orientational alignment of the molecular dipoles. Polarizable models of amide compounds that have two (acetamide) and zero (N,N-dimethyl acetamide) polar hydrogen-bond donor atoms are also investigated. Experimentally, the neat liquid dielectric constants at 373 K are 100 for NMA, 66 for acetamide and 26 for N,N-dimethyl acetamide. The polarizable models replicate this trend, predicting a dielectric constant of 92+/-5 for NMA, 66+/-3 for acetamide and 23+/-1 for N,N-dimethyl acetamide.

Improving the Prediction of Absolute Solvation Free Energies Using the Next Generation OPLS Force Field

Explicit solvent molecular dynamics free energy perturbation simulations were performed to predict absolute solvation free energies of 239 diverse small molecules. We use OPLS2.0, the next generation OPLS force field, and compare the results with popular small molecule force fields-OPLS_2005, GAFF, and CHARMm-MSI. OPLS2.0 produces the best correlation with experimental data (R(2) = 0.95, slope = 0.96) and the lowest average unsigned errors (0.7 kcal/mol). Important classes of compounds that performed suboptimally with OPLS_2005 show significant improvements.

A Polarizable Force Field of Dipalmitoylphosphatidylcholine based on the Classical Drude Model for Molecular Dynamics Simulations of Lipids

A polarizable force field of saturated phosphatidylcholine-containing lipids based on the classical Drude oscillator model is optimized and used in molecular dynamics simulations of bilayer and monolayer membranes. The hierarchical parametrization strategy involves the optimization of parameters for small molecules representative of lipid functional groups, followed by their application in larger model compounds and full lipids. The polar headgroup is based on molecular ions tetramethyl ammonium and dimethyl phosphate, the esterified glycerol backbone is based on methyl acetate, and the aliphatic lipid hydrocarbon tails are based on linear alkanes. Parameters, optimized to best represent a collection of gas and liquid properties for these compounds, are assembled into a complete model of dipalmitoylphosphatidylcholine (DPPC) lipids that is tested against the experimental properties of bilayer and monolayer membranes. The polarizable model yields average structural properties that are in broad accord with experimental data. The area per lipid of the model is 60 Å(2), slightly smaller than the experimental value of 63 Å(2). The order parameters from nuclear magnetic resonance deuterium quadrupolar splitting measures, the electron density profile, and the monolayer dipole potential are in reasonable agreement with experimental data, and with the nonpolarizable CHARMM C36 lipid force field.

Docking Covalent Inhibitors: A Parameter Free Approach To Pose Prediction and Scoring

Although many popular docking programs include a facility to account for covalent ligands, large-scale systematic docking validation studies of covalent inhibitors have been sparse. In this paper, we present the development and validation of a novel approach for docking and scoring covalent inhibitors, which consists of conventional noncovalent docking, heuristic formation of the covalent attachment point, and structural refinement of the protein-ligand complex. This approach combines the strengths of the docking program Glide and the protein structure modeling program Prime and does not require any parameter fitting for the study of additional covalent reaction types. We first test this method by predicting the native binding geometry of 38 covalently bound complexes. The average RMSD of the predicted poses is 1.52 Å, and 76% of test set inhibitors have an RMSD of less than 2.0 Å. In addition, the apparent affinity score constructed herein is tested on a virtual screening study and the characterization of the SAR properties of two different series of congeneric compounds with satisfactory success.

Many-body polarization effects and the membrane dipole potential.

Molecular dynamics simulations of a lipid monolayer at a water-air interface are used to investigate the dipole potential that arises at the water-lipid interface. One simulation explicitly accounts for many-body polarization effects by using a model based on classical Drude oscillators. The dipole potential of the Drude model monolayer is 0.35V in excellent agreement with experimental estimates that range between 0.3 and 0.4V, whereas, a simulation using a nonpolarizable model significantly overestimates the potential with a calculated value of 0.8V. Induced polarization effects in the nonpolar region of the monolayer are found to buffer the residual positive lipid potential that results from competing polarization effects at the polar water/monolayer interface. These results, indicate the utility of the inclusion of many-body polarization effects in empirical force field models of lipids.

Molecular Dynamics Study of a Polymeric Reverse Osmosis Membrane

Molecular dynamics (MD) simulations are used to investigate the properties of an atomic model of an aromatic polyamide reverse osmosis membrane. The monomers forming the polymeric membrane are cross-linked progressively on the basis of a heuristic distance criterion during MD simulations until the system interconnectivity reaches completion. Equilibrium MD simulations of the hydrated membrane are then used to determine the density and diffusivity of water within the membrane. Given a 3 MPa pressure differential and a 0.125 microm width membrane, the simulated water flux is calculated to be 1.4x10(-6) m/s, which is in fair agreement with an experimental flux measurement of 7.7x10(-6) m/s.

On the origin of the electrostatic potential difference at a liquid-vacuum interface

The microscopic origin of the interface potential calculated from computer simulations is elucidated by considering a simple model of molecules near an interface. The model posits that molecules are isotropically oriented and their charge density is Gaussian distributed. Molecules that have a charge density that is more negative toward their interior tend to give rise to a negative interface potential relative to the gaseous phase, while charge densities more positive toward their interior give rise to a positive interface potential. The interface potential for the model is compared to the interface potential computed from molecular dynamics simulations of the nonpolar vacuum-methane system and the polar vacuum-water interface system. The computed vacuum-methane interface potential from a molecular dynamics simulation (-220 mV) is captured with quantitative precision by the model. For the vacuum-water interface system, the model predicts a potential of -400 mV compared to -510 mV, calculated from a molecular dynamics simulation. The physical implications of this isotropic contribution to the interface potential is examined using the example of ion solvation in liquid methane.

Efficient Simulation Method for Polarizable Protein Force Fields: Application to the Simulation of BPTI in Liquid Water

A methodology for large scale molecular dynamics simulation of a solvated polarizable protein, using a combination of permanent and inducible point dipoles with fluctuating and fixed charges, is discussed and applied to the simulation of water solvated bovine pancreatic trypsin inhibitor (BPTI). The electrostatic forces are evaluated using a generalized form of the P3M Ewald method which includes point dipoles in addition to point charge sites. The electrostatic configuration is propagated along with the nuclei during the course of the simulation using an extended Lagrangian formalism. For the system size studied, 20000 atoms, this method gives only a marginal computational overhead relative to nonpolarizable potential models (1.23-1.45) per time step of simulation. The models employ a newly developed polarizable dipole force field for the protein(1) with two commonly used water models TIP4P-FQ and RPOL. Performed at constant energy and constant volume (NVE) using the velocity Verlet algorithm, the simulations show excellent energy conservation and run stably for their 2 ns duration. To characterize the accuracy of the solvation models the protein structure is analyzed. The simulated structures remain within 1 Å of the experimental crystal structure for the duration of the simulation in line with the nonpolarizable OPLS-AA model.