title: Prediction of cyclohexane-water distribution coefficients for the SAMPL5 data set using molecular dynamics simulations with the OPLS-AA force field.
abstract: All-atom molecular dynamics simulations were used to predict water-cyclohexane distribution coefficients [Formula: see text] of a range of small molecules as part of the SAMPL5 blind prediction challenge. Molecules were parameterized with the transferable all-atom OPLS-AA force field, which required the derivation of new parameters for sulfamides and heterocycles and validation of cyclohexane parameters as a solvent. The distribution coefficient was calculated from the solvation free energies of the compound in water and cyclohexane. Absolute solvation free energies were computed by an established protocol using windowed alchemical free energy perturbation with thermodynamic integration. This protocol resulted in an overall root mean square error in [Formula: see text] of almost 4 log units and an overall signed error of -3 compared to experimental data. There was no substantial overall difference in accuracy between simulating in NVT and NPT ensembles. The signed error suggests a systematic error but the experimental [Formula: see text] data on their own are insufficient to uncover the source of this error. Preliminary work suggests that the major source of error lies in the hydration free energy calculations.
authors: Department of Physics, Arizona State University, P.O. Box 871504, Tempe, AZ, 85287-1504, USA.
authors: Ian M
authors: IM
authors: Kenney
authors: Department of Physics, Arizona State University, P.O. Box 871504, Tempe, AZ, 85287-1504, USA. oliver.beckstein@asu.edu.|Center for Biological Physics, Arizona State University, P.O. Box 871504, Tempe, AZ, 85287-1504, USA. oliver.beckstein@asu.edu.
authors: Oliver
authors: 0000-0003-1340-0831
authors: O
authors: Beckstein
authors: Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Université Paris-Saclay, Labex LERMIT, 1 Avenue de la Terrasse, 91198, Gif-sur-Yvette, France. bogdan.iorga@cnrs.fr.
authors: Bogdan I
authors: 0000-0003-0392-1350
authors: BI
authors: Iorga
mesh_terms: D003510:Cyclohexanes / Q000737:chemistry*; D008956:Models, Chemical; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D012995:Solubility; D012997:Solvents / Q000737:chemistry; D013816:Thermodynamics; D014867:Water / Q000737:chemistry*
chemical_list: D003510:Cyclohexanes; D004364:Pharmaceutical Preparations; D012997:Solvents; D014867:Water; C506365:Cyclohexane
keywords: Cyclohexane-water distribution coefficients; Free energy perturbation; Ligand parameterization; Molecular dynamics; OPLS-AA force field; Solvation free energy; Thermodynamic integration