The principal challenge of using classical physics to model biomolecular interactions is capturing the nature of short-range interactions that drive biological processes from nucleic acid base stacking to protein–ligand binding. In particular most classical force fields suffer from an error in their electrostatic models that arises from an ability to account for the overlap between charge distributions occurring when molecules get close to each other, known as charge penetration. In this work we present a simple, physically motivated model for including charge penetration in the AMOEBA (Atomic Multipole Optimized Energetics for Biomolecular Applications) force field. With a function derived from the charge distribution of a hydrogen-like atom and a limited number of parameters, our charge penetration model dramatically improves the description of electrostatics at short range. On a database of 101 biomolecular dimers, the charge penetration model brings the error in the electrostatic interaction energy relative to the ab initio SAPT electrostatic interaction energy from 13.4 kcal mol−1 to 1.3 kcal mol−1. The model is shown not only to be robust and transferable for the AMOEBA model, but also physically meaningful as it universally improves the description of the electrostatic potential around a given molecule.

A set of improved parameters for the AMOEBA polarizable atomic multipole water model is developed. An automated procedure, ForceBalance, is used to adjust model parameters to enforce agreement with ab initio-derived results for water clusters and experimental data for a variety of liquid phase properties across a broad temperature range. The values reported here for the new AMOEBA14 water model represent a substantial improvement over the previous AMOEBA03 model. The AMOEBA14 model accurately predicts the temperature of maximum density and qualitatively matches the experimental density curve across temperatures from 249 to 373 K. Excellent agreement is observed for the AMOEBA14 model in comparison to experimental properties as a function of temperature, including the second virial coefficient, enthalpy of vaporization, isothermal compressibility, thermal expansion coefficient, and dielectric constant. The viscosity, self-diffusion constant, and surface tension are also well reproduced. In comparison to high-level ab initio results for clusters of 2–20 water molecules, the AMOEBA14 model yields results similar to AMOEBA03 and the direct polarization iAMOEBA models. With advances in computing power, calibration data, and optimization techniques, we recommend the use of the AMOEBA14 water model for future studies employing a polarizable water model.

An extensible polarizable force field for transition-metal ions was developed based on AMOEBA and the angular overlap model (AOM) with consistent treatment of electrostatics for all atoms. Parameters were obtained by fitting molecular mechanics (MM) energies to various ab initio gas-phase calculations. The results of parametrization were presented for copper(II) ion ligated to water and model fragments of amino acid residues involved in the copper binding sites of type 1 copper proteins. Molecular dynamics (MD) simulations were performed on aqueous copper(II) ion at various temperatures as well as plastocyanin (1AG6) and azurin (1DYZ). Results demonstrated that the AMOEBA-AOM significantly improves the accuracy of classical MM in a number of test cases when compared to ab initio calculations. The Jahn–Teller distortion for hexa-aqua copper(II) complex was handled automatically without specifically designating axial and in-plane ligands. Analyses of MD trajectories resulted in a six-coordination first solvation shell for aqueous copper(II) ion and a 1.8 ns average residence time of water molecules. The ensemble average geometries of 1AG6 and 1DYZ copper binding sites were in general agreement with X-ray and previous computational studies.

An empirical potential based on permanent atomic multipoles and atomic induced dipoles is reported for alkanes, alcohols, amines, sulfides, aldehydes, carboxylic acids, amides, aromatics, and other small organic molecules. Permanent atomic multipole moments through quadrupole moments have been derived from gas phase ab initio molecular orbital calculations. The van der Waals parameters are obtained by fitting to gas phase homodimer QM energies and structures, as well as experimental densities and heats of vaporization of neat liquids. As a validation, the hydrogen bonding energies and structures of gas phase heterodimers with water are evaluated using the resulting potential. For 32 homo- and heterodimers, the association energy agrees with ab initio results to within 0.4 kcal/mol. The RMS deviation of the hydrogen bond distance from QM optimized geometry is less than 0.06 Å. In addition, liquid self-diffusion and static dielectric constants computed from a molecular dynamics simulation are consistent with experimental values. The force field is also used to compute the solvation free energy of 27 compounds not included in the parametrization process, with a RMS error of 0.69 kcal/mol. The results obtained in this study suggest that the AMOEBA force field performs well across different environments and phases. The key algorithms involved in the electrostatic model and a protocol for developing parameters are detailed to facilitate extension to additional molecular systems.

Potential smoothing, a deterministic analog of stochastic simulated annealing, is a powerful paradigm for the solution of conformational search problems that require extensive sampling, and should be a useful tool in computational approaches to structure prediction and refinement. A novel potential smoothing and search (PSS) algorithm has been developed and applied to predict the packing of transmembrane helices. The highlight of this method is the efficient manner in which it circumvents the combinatorial explosion associated with the large number of minima on multidimensional potential energy surfaces in order to converge to the global energy minimum. Here we show how our potential smoothing and search method succeeds in finding the global minimum energy structure for the glycophorin A (GpA) transmembrane helix dimer by optimizing interhelical van der Waals interactions over rigid and semi−rigid helices. Structures obtained from our ab initio predictions are in close agreement with recent experimental data.

The principal challenge of using classical physics to model biomolecular interactions is capturing the nature of short-range interactions that drive biological processes from nucleic acid base stacking to protein–ligand binding. In particular most classical force fields suffer from an error in their electrostatic models that arises from an ability to account for the overlap between charge distributions occurring when molecules get close to each other, known as charge penetration. In this work we present a simple, physically motivated model for including charge penetration in the AMOEBA (Atomic Multipole Optimized Energetics for Biomolecular Applications) force field. With a function derived from the charge distribution of a hydrogen-like atom and a limited number of parameters, our charge penetration model dramatically improves the description of electrostatics at short range. On a database of 101 biomolecular dimers, the charge penetration model brings the error in the electrostatic interaction energy relative to the ab initio SAPT electrostatic interaction energy from 13.4 kcal mol−1 to 1.3 kcal mol−1. The model is shown not only to be robust and transferable for the AMOEBA model, but also physically meaningful as it universally improves the description of the electrostatic potential around a given molecule.