Extremely precise free energy calculations of amino acid side chain analogs: Comparison of common molecular mechanics force fields for proteins Computational techniques see widespread use in pharmaceutical drug discovery, but typically prove unreliable in predicting trends in protein-ligand binding. Alchemical free energy calculations seek to change that by providing rigorous binding free energies from molecular simulations. Given adequate sampling and an accurate enough force field, these techniques yield accurate free energy estimates. Recent innovations in alchemical techniques have sparked a resurgence of interest in these calculations. Still, many obstacles stand in the way of their routine application in a drug discovery context, including the one we focus on here, sampling. Sampling of binding modes poses a particular challenge as binding modes are often separated by large energy barriers, leading to slow transitions. Binding modes are difficult to predict, and in some cases multiple binding modes may contribute to binding. In view of these hurdles, we present a framework for dealing carefully with uncertainty in binding mode or conformation in the context of free energy calculations. With careful sampling, free energy techniques show considerable promise for aiding drug discovery.

A re-parameterization of the standard TIP4P water model for use with Ewald techniques is introduced, providing an overall global improvement in water properties relative to several popular nonpolarizable and polarizable water potentials. Using high precision simulations, and careful application of standard analytical corrections, we show that the new TIP4P-Ew potential has a density maximum at approximately 1 degrees C, and reproduces experimental bulk-densities and the enthalpy of vaporization, DeltaH(vap), from -37.5 to 127 degrees C at 1 atm with an absolute average error of less than 1%. Structural properties are in very good agreement with x-ray scattering intensities at temperatures between 0 and 77 degrees C and dynamical properties such as self-diffusion coefficient are in excellent agreement with experiment. The parameterization approach used can be easily generalized to rehabilitate any water force field using available experimental data over a range of thermodynamic points.

Optimized intermolecular potential functions have been determined for hydrocarbons through Monte Carlo simulations of 15 liquids: methane, ethane, propane, n-butane, isobutane, n-pentane, isopentane, neopentane, cyclopentane, n-hexane, 1 -butene, cis-and trans-2-butene, isobutene, and benzene. To achieve high accuracy, 12 unique group types were identified and their associated Lennard-Jones parameters were established. The average deviation from experiment for the computed densities and heats of vaporization is 2% and trends for isomeric series are reproduced. Conformational results were also obtained for five liquids and revealed no condensed-phase effects on the conformer populations. Structural analyses focus on trends as a function of chain length and branching of the monomers.

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