title: Blind prediction of distribution in the SAMPL5 challenge with QM based protomer and pKacorrections.
abstract: The computation of distribution coefficients between polar and apolar phases requires both an accurate characterization of transfer free energies between phases and proper accounting of ionization and protomerization. We present a protocol for accurately predicting partition coefficients between two immiscible phases, and then apply it to 53 drug-like molecules in the SAMPL5 blind prediction challenge. Our results combine implicit solvent QM calculations with classical MD simulations using the non-Boltzmann Bennett free energy estimator. The OLYP/DZP/SMD method yields predictions that have a small deviation from experiment (RMSD = 2.3 [Formula: see text] D units), relative to other participants in the challenge. Our free energy corrections based on QM protomer and [Formula: see text] calculations increase the correlation between predicted and experimental distribution coefficients, for all methods used. Unfortunately, these corrections are overly hydrophilic, and fail to account for additional effects such as aggregation, water dragging and the presence of polar impurities in the apolar phase. We show that, although expensive, QM-NBB free energy calculations offer an accurate and robust method that is superior to standard MM and QM techniques alone.
authors.affiliation: Laboratory of Computational Biology, National Institutes of Health - National Heart, Lung and Blood Institute, 5635 Fishers Lane, T-900 Suite, Rockville, MD, 20852, USA. frank.pickard@nih.gov.
authors.forename: Frank C
authors.identifier: 0000-0002-9608-3466
authors.initials: FC
authors.lastname: Pickard
authors.affiliation: Laboratory of Computational Biology, National Institutes of Health - National Heart, Lung and Blood Institute, 5635 Fishers Lane, T-900 Suite, Rockville, MD, 20852, USA.|Max Planck Institut für Kohlenforschung, 45470, Mülheim an der Ruhr, NRW, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: König
authors.affiliation: Laboratory of Computational Biology, National Institutes of Health - National Heart, Lung and Blood Institute, 5635 Fishers Lane, T-900 Suite, Rockville, MD, 20852, USA.
authors.forename: Florentina
authors.initials: F
authors.lastname: Tofoleanu
authors.affiliation: Laboratory of Computational Biology, National Institutes of Health - National Heart, Lung and Blood Institute, 5635 Fishers Lane, T-900 Suite, Rockville, MD, 20852, USA.
authors.forename: Juyong
authors.initials: J
authors.lastname: Lee
authors.affiliation: Laboratory of Computational Biology, National Institutes of Health - National Heart, Lung and Blood Institute, 5635 Fishers Lane, T-900 Suite, Rockville, MD, 20852, USA.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Simmonett
authors.affiliation: Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK, 73019, USA.
authors.forename: Yihan
authors.initials: Y
authors.lastname: Shao
authors.affiliation: Department of Chemistry, Washington University, St. Louis, MO, 63130, USA.
authors.forename: Jay W
authors.initials: JW
authors.lastname: Ponder
authors.affiliation: Laboratory of Computational Biology, National Institutes of Health - National Heart, Lung and Blood Institute, 5635 Fishers Lane, T-900 Suite, Rockville, MD, 20852, USA.
authors.forename: Bernard R
authors.initials: BR
authors.lastname: Brooks
mesh_terms: D003198:Computer Simulation; D003510:Cyclohexanes / Q000737:chemistry; D008956:Models, Chemical; D056004:Molecular Dynamics Simulation; 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: Distribution coefficients; Free energy; Implicit solvent; Non-Boltzmann Bennett; Partition coefficients; Protomer; SAMPL5; Tautomer; pKa