Prediction of cyclohexane-water distribution coefficients for the SAMPL5 data set using molecular dynamics simulations with the OPLS-AA force field

• Published in: Journal of computer-aided molecular design Vol. 30; no. 11; pp. 1045 - 1058
• Main Authors: Kenney, Ian M., Beckstein, Oliver, Iorga, Bogdan I.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.11.2016; Springer Nature B.V; Springer Verlag
• Subjects: Animal Anatomy; Aqueous chemistry; Chemical Sciences; Chemistry; Chemistry and Materials Science; Computer Applications in Chemistry; Computer simulation; Cyclohexane; Cyclohexanes - chemistry; Errors; Free energy; Histology; Hydrophobic surfaces; Ligands; Mathematical analysis; Models, Chemical; Molecular dynamics; Molecular Dynamics Simulation; Molecular physics; Molecular Structure; Morphology; or physical chemistry; Parameters; Pharmaceutical Preparations - chemistry; Physical Chemistry; Solubility; Solvation; Solvents; Solvents - chemistry; Theoretical and; Thermodynamics; Water - chemistry; Solvation free energy; Free energy perturbation; Cyclohexane-water distribution coefficients; Molecular dynamics; OPLS-AA force field; Thermodynamic integration; Ligand parameterization
• ISSN: 0920-654X; 1573-4951
• DOI: 10.1007/s10822-016-9949-5

All-atom molecular dynamics simulations were used to predict water-cyclohexane distribution coefficients D c w 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 log D c w 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 D c w 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.