title: Calculating distribution coefficients based on multi-scale free energy simulations: an evaluation of MM and QM/MM explicit solvent simulations of water-cyclohexane transfer in the SAMPL5 challenge.
abstract: One of the central aspects of biomolecular recognition is the hydrophobic effect, which is experimentally evaluated by measuring the distribution coefficients of compounds between polar and apolar phases. We use our predictions of the distribution coefficients between water and cyclohexane from the SAMPL5 challenge to estimate the hydrophobicity of different explicit solvent simulation techniques. Based on molecular dynamics trajectories with the CHARMM General Force Field, we compare pure molecular mechanics (MM) with quantum-mechanical (QM) calculations based on QM/MM schemes that treat the solvent at the MM level. We perform QM/MM with both density functional theory (BLYP) and semi-empirical methods (OM1, OM2, OM3, PM3). The calculations also serve to test the sensitivity of partition coefficients to solute polarizability as well as the interplay of the quantum-mechanical region with the fixed-charge molecular mechanics environment. Our results indicate that QM/MM with both BLYP and OM2 outperforms pure MM. However, this observation is limited to a subset of cases where convergence of the free energy can be achieved.
authors: Laboratory of Computational Biology, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA. gkoenig@mpi-muelheim.mpg.de.|Max-Planck-Institut für Kohlenforschung, 45470, Mülheim an der Ruhr, Germany. gkoenig@mpi-muelheim.mpg.de.
authors: Gerhard
authors: G
authors: König
authors: Laboratory of Computational Biology, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
authors: Frank C
authors: FC
authors: Pickard
authors: Laboratory of Computational Biology, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
authors: Jing
authors: J
authors: Huang
authors: Laboratory of Computational Biology, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
authors: Andrew C
authors: AC
authors: Simmonett
authors: Laboratory of Computational Biology, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
authors: Florentina
authors: F
authors: Tofoleanu
authors: Laboratory of Computational Biology, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
authors: Juyong
authors: J
authors: Lee
authors: Max-Planck-Institut für Kohlenforschung, 45470, Mülheim an der Ruhr, Germany.
authors: Pavlo O
authors: PO
authors: Dral
authors: Laboratory of Computational Biology, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
authors: Samarjeet
authors: S
authors: Prasad
authors: Laboratory of Computational Biology, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
authors: Michael
authors: M
authors: Jones
authors: Laboratory of Computational Biology, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
authors: Yihan
authors: Y
authors: Shao
authors: Max-Planck-Institut für Kohlenforschung, 45470, Mülheim an der Ruhr, Germany.
authors: Walter
authors: W
authors: Thiel
authors: Laboratory of Computational Biology, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
authors: Bernard R
authors: BR
authors: Brooks
mesh_terms: D003198:Computer Simulation; D003510:Cyclohexanes / Q000737:chemistry*; D008956:Models, Chemical; D015394:Molecular Structure; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D011789:Quantum Theory; 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; Distribution coefficient; Explicit solvent; Multi-scale free energy simulations; Partition coefficient; Water