(457e) Direct Calculation of 1-Octanol–Water Partition Coefficients From Adaptive Biasing Force Molecular Dynamics Simulations

The 1–octanol–water partition coefficient log K_ow of a solute is a key parameter used in the prediction of a wide variety of complex phenomena such as drug availability and bioaccumulation potential of trace contaminants. In this work, the application of adaptive biasing force molecular dynamics simulations (ABF–MD)^1-4 to the calculation of 1-octanol-water partition coefficients is presented.  Unlike traditional methods, such as thermodynamic integration and free energy perturbation, which produce relative free energy values, the ABF-MD method predicts absolute free energies of transfer and eliminates the need for reference solutes.  Two approaches are evaluated; the direct transfer of the solute from 1–octanol to water phase, and separate transfers of the solute from the water or 1–octanol phase to vacuum, with both methods yielding statistically indistinguishable results.   Simulations performed on a variety of system sizes are used to show that the calculated potential of mean force is remarkably insensitive to the microstructure of the solvent, a finding that suggests relatively small system sizes may be used to determine accurate free energies of transfer.  The effect of various simulation parameters on the sampling efficiency is discussed.

Calculations are performed on a variety of systems, including n-alkanes, alcohols, chemical warfare agents, energetic materials and ionic liquids. The effect of wet vs. dry octanol and choice of water model is assessed for each system.   The predictions of ABF-MD are found to be in excellent agreement with prior calculations performed with thermodynamic integration⁵ or Gibbs ensemble Monte Carlo⁶.

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