title: SAMPL5: 3D-RISM partition coefficient calculations with partial molar volume corrections and solute conformational sampling.
abstract: Implicit solvent methods for classical molecular modeling are frequently used to provide fast, physics-based hydration free energies of macromolecules. Less commonly considered is the transferability of these methods to other solvents. The Statistical Assessment of Modeling of Proteins and Ligands 5 (SAMPL5) distribution coefficient dataset and the accompanying explicit solvent partition coefficient reference calculations provide a direct test of solvent model transferability. Here we use the 3D reference interaction site model (3D-RISM) statistical-mechanical solvation theory, with a well tested water model and a new united atom cyclohexane model, to calculate partition coefficients for the SAMPL5 dataset. The cyclohexane model performed well in training and testing ([Formula: see text] for amino acid neutral side chain analogues) but only if a parameterized solvation free energy correction was used. In contrast, the same protocol, using single solute conformations, performed poorly on the SAMPL5 dataset, obtaining [Formula: see text] compared to the reference partition coefficients, likely due to the much larger solute sizes. Including solute conformational sampling through molecular dynamics coupled with 3D-RISM (MD/3D-RISM) improved agreement with the reference calculation to [Formula: see text]. Since our initial calculations only considered partition coefficients and not distribution coefficients, solute sampling provided little benefit comparing against experiment, where ionized and tautomer states are more important. Applying a simple [Formula: see text] correction improved agreement with experiment from [Formula: see text] to [Formula: see text], despite a small number of outliers. Better agreement is possible by accounting for tautomers and improving the ionization correction.
authors: Department of Physics and Astronomy, California State University, Northridge, Northridge, CA, 91330-8268, USA. tluchko@csun.edu.
authors: Tyler
authors: 0000-0001-6737-6019
authors: T
authors: Luchko
authors: National Institute for Nanotechnology, National Research Council of Canada, 11421 Saskatchewan Dr., Edmonton, AB, T6G 2M9, Canada.|Department of Mechanical Engineering, University of Alberta, 10-203 Donadeo Innovation Centre for Engineering, 9211-116 Str., Edmonton, AB, T6G 1H9, Canada.
authors: Nikolay
authors: N
authors: Blinov
authors: Department of Physics and Astronomy, California State University, Northridge, Northridge, CA, 91330-8268, USA.
authors: Garrett C
authors: GC
authors: Limon
authors: Department of Physics and Astronomy, California State University, Northridge, Northridge, CA, 91330-8268, USA.
authors: Kevin P
authors: KP
authors: Joyce
authors: National Institute for Nanotechnology, National Research Council of Canada, 11421 Saskatchewan Dr., Edmonton, AB, T6G 2M9, Canada.|Department of Mechanical Engineering, University of Alberta, 10-203 Donadeo Innovation Centre for Engineering, 9211-116 Str., Edmonton, AB, T6G 1H9, Canada.
authors: Andriy
authors: A
authors: Kovalenko
mesh_terms: D003198:Computer Simulation; D003510:Cyclohexanes / Q000737:chemistry*; D007536:Isomerism; D008956:Models, Chemical; D008968:Molecular Conformation; 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: 3D-RISM; Cyclohexane; Molecular dynamics; Multiple time step; Partial molar volume; Partition coefficient; Solvent force extrapolation; Water