Precise force-field-based calculations of octanol-water partition coefficients for the SAMPL7 molecules.

ABSTRACT

We predicted water-octanol partition coefficients for the molecules in the SAMPL7 challenge with explicit solvent classical molecular dynamics (MD) simulations. Water hydration free energies and octanol solvation free energies were calculated with a windowed alchemical free energy approach. Three commonly used force fields (AMBER GAFF, CHARMM CGenFF, OPLS-AA) were tested. Special emphasis was placed on converging all simulations, using a criterion developed for the SAMPL6 challenge. In aggregate, over 1000 [Formula see text]s of simulations were performed, with some free energy windows remaining not fully converged even after 1 [Formula see text]s of simulation time. Nevertheless, the amount of sampling produced [Formula see text] estimates with a precision of 0.1 log units or better for converged simulations. Despite being probably as fully sampled as can expected and is feasible, the agreement with experiment remained modest for all force fields, with no force field performing better than 1.6 in root mean squared error. Overall, our results indicate that a large amount of sampling is necessary to produce precise [Formula see text] predictions for the SAMPL7 compounds and that high precision does not necessarily lead to high accuracy. Thus, fundamental problems remain to be solved for physics-based [Formula see text] predictions.