Dataset Information

Calculating Partition Coefficients of Small Molecules in Octanol/Water and Cyclohexane/Water.

ABSTRACT: Partition coefficients describe how a solute is distributed between two immiscible solvents. They are used in drug design as a measure of a solute's hydrophobicity and a proxy for its membrane permeability. We calculate partition coefficients from transfer free energies using molecular dynamics simulations in explicit solvent. Setup is done by our new Solvation Toolkit which automates the process of creating input files for any combination of solutes and solvents for many popular molecular dynamics software packages. We calculate partition coefficients between octanol/water and cyclohexane/water with the Generalized AMBER Force Field (GAFF) and the Dielectric Corrected GAFF (GAFF-DC). With similar methods in the past we found a root-mean-squared error (RMSE) of 6.3 kJ/mol in hydration free energies which would correspond to an error of around 1.6 log units in partition coefficients if solvation free energies in both solvents were estimated with comparable accuracy. Here we find an overall RMSE of about 1.2 log units with both force fields. Results from GAFF and GAFF-DC seem to exhibit systematic biases in opposite directions for calculated cyclohexane/water partition coefficients.

SUBMITTER: Bannan CC

PROVIDER: S-EPMC5053177 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Calculating Partition Coefficients of Small Molecules in Octanol/Water and Cyclohexane/Water.

Bannan Caitlin C CC Calabró Gaetano G Kyu Daisy Y DY Mobley David L DL

Journal of chemical theory and computation 20160801 8

Partition coefficients describe how a solute is distributed between two immiscible solvents. They are used in drug design as a measure of a solute's hydrophobicity and a proxy for its membrane permeability. We calculate partition coefficients from transfer free energies using molecular dynamics simulations in explicit solvent. Setup is done by our new Solvation Toolkit which automates the process of creating input files for any combination of solutes and solvents for many popular molecular dynam ...[more]

PMID: 27434695

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Project description:All-atom molecular dynamics simulations with stratified alchemical free energy calculations were used to predict the octanol-water partition coefficient [Formula: see text] of eleven small molecules as part of the SAMPL6-[Formula: see text] blind prediction challenge using four different force field parametrizations: standard OPLS-AA with transferable charges, OPLS-AA with non-transferable CM1A charges, AMBER/GAFF, and CHARMM/CGenFF. Octanol parameters for OPLS-AA, GAFF and CHARMM were validated by comparing the density as a function of temperature, the chemical potential, and the hydration free energy to experimental values. The partition coefficients were calculated from the solvation free energy for the compounds in water and pure ("dry") octanol or "wet" octanol with 27 mol% water dissolved. Absolute solvation free energies were computed by thermodynamic integration (TI) and the multistate Bennett acceptance ratio with uncorrelated samples from data generated by an established protocol using 5-ns windowed alchemical free energy perturbation (FEP) calculations with the Gromacs molecular dynamics package. Equilibration of sets of FEP simulations was quantified by a new measure of convergence based on the analysis of forward and time-reversed trajectories. The accuracy of the [Formula: see text] predictions was assessed by descriptive statistical measures such as the root mean square error (RMSE) of the data set compared to the experimental values. Discarding the first 1 ns of each 5-ns window as an equilibration phase had a large effect on the GAFF data, where it improved the RMSE by up to 0.8 log units, while the effect for other data sets was smaller or marginally worsened the agreement. Overall, CGenFF gave the best prediction with RMSE 1.2 log units, although for only eight molecules because the current CGenFF workflow for Gromacs does not generate files for certain halogen-containing compounds. Over all eleven compounds, GAFF gave an RMSE of 1.5. The effect of using a mixed water/octanol solvent slightly decreased the accuracy for CGenFF and GAFF and slightly increased it for OPLS-AA. The GAFF and OPLS-AA results displayed a systematic error where molecules were too hydrophobic whereas CGenFF appeared to be more balanced, at least on this small data set.

Dataset Information

Calculating Partition Coefficients of Small Molecules in Octanol/Water and Cyclohexane/Water.

Publications

Calculating Partition Coefficients of Small Molecules in Octanol/Water and Cyclohexane/Water.

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