Prediction of cyclohexane-water distribution coefficient for SAMPL5 drug-like compounds with the QMPFF3 and ARROW polarizable force fields

We present the performance of blind predictions of water—cyclohexane distribution coefficients for 53 drug-like compounds in the SAMPL5 challenge by three methods currently in use within our group. Two of them utilize QMPFF3 and ARROW, polarizable force-fields of varying complexity, and the third uses the General Amber Force-Field (GAFF). The polarizable FF’s are implemented in an in-house MD package, Arbalest. We find that when we had time to parametrize the functional groups with care (batch 0), the polarizable force-fields outperformed the non-polarizable one. Conversely, on the full set of 53 compounds, GAFF performed better than both QMPFF3 and ARROW. We also describe the torsion-restrain method we used to improve sampling of molecular conformational space and thus the overall accuracy of prediction. The SAMPL5 challenge highlighted several drawbacks of our force-fields, such as our significant systematic over-estimation of hydrophobic interactions, specifically for alkanes and aromatic rings.

[1]  A. Misquitta,et al.  Charge Transfer from Regularized Symmetry-Adapted Perturbation Theory. , 2013, Journal of chemical theory and computation.

[2]  A. V. Finkelstein,et al.  Development and testing of PFFSol1.1, a new polarizable atomic force field for calculation of molecular interactions in implicit water environment. , 2012, The journal of physical chemistry. B.

[3]  Alexander D. MacKerell,et al.  CHARMM fluctuating charge force field for proteins: II Protein/solvent properties from molecular dynamics simulations using a nonadditive electrostatic model , 2004, J. Comput. Chem..

[4]  Nikolay G. Galkin,et al.  Assessment of performance of the general purpose polarizable force field QMPFF3 in condensed phase , 2008, J. Comput. Chem..

[5]  Jonah Z. Vilseck,et al.  Biomolecular Force Field Parameterization via Atoms-in-Molecule Electron Density Partitioning , 2016, Journal of chemical theory and computation.

[6]  Nikolay Galkin,et al.  Application of a polarizable force field to calculations of relative protein–ligand binding affinities , 2008, Proceedings of the National Academy of Sciences.

[7]  J. Applequist,et al.  Atom charge transfer in molecular polarizabilities: application of the Olson-Sundberg model to aliphatic and aromatic hydrocarbons , 1993 .

[8]  Hoover,et al.  Canonical dynamics: Equilibrium phase-space distributions. , 1985, Physical review. A, General physics.

[9]  T. Halgren,et al.  Polarizable force fields. , 2001, Current opinion in structural biology.

[10]  Margaret E. Johnson,et al.  Current status of the AMOEBA polarizable force field. , 2010, The journal of physical chemistry. B.

[11]  M. Levitt,et al.  Refinement of protein conformations using a macromolecular energy minimization procedure. , 1969, Journal of molecular biology.

[12]  Pengyu Y. Ren,et al.  Polarizable Atomic Multipole Water Model for Molecular Mechanics Simulation , 2003 .

[13]  Matthew T. Geballe,et al.  The SAMPL3 blind prediction challenge: transfer energy overview , 2012, Journal of Computer-Aided Molecular Design.

[14]  Justin L. MacCallum,et al.  Calculation of the water–cyclohexane transfer free energies of neutral amino acid side‐chain analogs using the OPLS all‐atom force field , 2003, J. Comput. Chem..

[15]  Steven J. Stuart,et al.  Dynamical fluctuating charge force fields: Application to liquid water , 1994 .

[16]  S. Nosé.  A unified formulation of the constant temperature molecular dynamics methods , 1984 .

[17]  David L Mobley,et al.  Predicting small-molecule solvation free energies: an informal blind test for computational chemistry. , 2008, Journal of medicinal chemistry.

[18]  David L. Mobley,et al.  Measuring experimental cyclohexane-water distribution coefficients for the SAMPL5 challenge , 2016, bioRxiv.

[19]  C. Chabalowski,et al.  Using Kohn−Sham Orbitals in Symmetry-Adapted Perturbation Theory to Investigate Intermolecular Interactions , 2001 .

[20]  M. V. Subbotin,et al.  A quantum mechanical polarizable force field for biomolecular interactions , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[21]  Gerrit Groenhof,et al.  GROMACS: Fast, flexible, and free , 2005, J. Comput. Chem..

[22]  Nohad Gresh,et al.  Key role of the polarization anisotropy of water in modeling classical polarizable force fields. , 2007, The journal of physical chemistry. A.

[23]  J. Ilja Siepmann,et al.  Transferable Potentials for Phase Equilibria. 1. United-Atom Description of n-Alkanes , 1998 .

[24]  Alexander D. MacKerell,et al.  Determination of Electrostatic Parameters for a Polarizable Force Field Based on the Classical Drude Oscillator. , 2005, Journal of chemical theory and computation.

[25]  Krzysztof Szalewicz,et al.  Intermolecular forces from asymptotically corrected density functional description of monomers , 2002 .

[26]  G Andrés Cisneros,et al.  Application of Gaussian Electrostatic Model (GEM) Distributed Multipoles in the AMOEBA Force Field. , 2012, Journal of chemical theory and computation.

[27]  Jan Řezáč,et al.  Extrapolation and Scaling of the DFT-SAPT Interaction Energies toward the Basis Set Limit. , 2011, Journal of chemical theory and computation.

[28]  Anthony Nicholls,et al.  The SAMPL2 blind prediction challenge: introduction and overview , 2010, J. Comput. Aided Mol. Des..

[29]  A. Klamt,et al.  COSMO-RS: a novel and efficient method for the a priori prediction of thermophysical data of liquids , 2000 .

[30]  Arieh Warshel,et al.  Polarizable Force Fields:  History, Test Cases, and Prospects. , 2007, Journal of chemical theory and computation.

[31]  Alessandra Villa,et al.  Calculation of the free energy of solvation for neutral analogs of amino acid side chains , 2002, J. Comput. Chem..

[32]  Krzysztof Szalewicz,et al.  Dispersion energy from density-functional theory description of monomers. , 2003, Physical review letters.

[33]  Charles L. Brooks,et al.  CHARMM fluctuating charge force field for proteins: I parameterization and application to bulk organic liquid simulations , 2004, J. Comput. Chem..

[34]  W. L. Jorgensen,et al.  The OPLS [optimized potentials for liquid simulations] potential functions for proteins, energy minimizations for crystals of cyclic peptides and crambin. , 1988, Journal of the American Chemical Society.

[35]  David L. Mobley,et al.  Blind prediction of cyclohexane–water distribution coefficients from the SAMPL5 challenge , 2016, Journal of Computer-Aided Molecular Design.

[36]  Alexander D. MacKerell,et al.  All-atom empirical potential for molecular modeling and dynamics studies of proteins. , 1998, The journal of physical chemistry. B.

[37]  Nohad Gresh,et al.  Improved Formulas for the Calculation of the Electrostatic Contribution to the Intermolecular Interaction Energy from Multipolar Expansion of the Electronic Distribution. , 2003, The journal of physical chemistry. A.

[38]  B. Fain,et al.  Polarizable Force Fields for Proteins , 2014 .

[39]  Richard Wolfenden,et al.  Comparing the polarities of the amino acids: side-chain distribution coefficients between the vapor phase, cyclohexane, 1-octanol, and neutral aqueous solution , 1988 .

[40]  M. V. Subbotin,et al.  Water properties from first principles: simulations by a general-purpose quantum mechanical polarizable force field. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[41]  T. Halgren.  Merck molecular force field. I. Basis, form, scope, parameterization, and performance of MMFF94 , 1996, J. Comput. Chem..

[42]  J. Kästner.  Umbrella sampling , 2011 .

[43]  T. Darden,et al.  Towards a force field based on density fitting. , 2006, The Journal of chemical physics.

[44]  A. Hagler.  Quantum Derivative Fitting and Biomolecular Force Fields: Functional Form, Coupling Terms, Charge Flux, Nonbond Anharmonicity, and Individual Dihedral Potentials. , 2015, Journal of chemical theory and computation.

[45]  R. Swendsen,et al.  THE weighted histogram analysis method for free‐energy calculations on biomolecules. I. The method , 1992 .

[46]  P. Kollman,et al.  An all atom force field for simulations of proteins and nucleic acids , 1986, Journal of computational chemistry.

[47]  H. Berendsen,et al.  Molecular dynamics with coupling to an external bath , 1984 .

[48]  Martin Schütz,et al.  Molpro: a general‐purpose quantum chemistry program package , 2012 .

[49]  Pengyu Y. Ren,et al.  The Polarizable Atomic Multipole-based AMOEBA Force Field for Proteins. , 2013, Journal of chemical theory and computation.

[50]  David L. Mobley,et al.  Blind prediction of solvation free energies from the SAMPL4 challenge , 2014, Journal of Computer-Aided Molecular Design.

[51]  V I Tarasov,et al.  Quantum mechanical polarizable force field (QMPFF3): refinement and validation of the dispersion interaction for aromatic carbon. , 2006, The Journal of chemical physics.

[52]  Alexander D. MacKerell,et al.  Polarizable empirical force field for the primary and secondary alcohol series based on the classical Drude model. , 2007, Journal of chemical theory and computation.

[53]  W. L. Jorgensen,et al.  Development and Testing of the OPLS All-Atom Force Field on Conformational Energetics and Properties of Organic Liquids , 1996 .

[54]  P. Kollman,et al.  A Second Generation Force Field for the Simulation of Proteins, Nucleic Acids, and Organic Molecules , 1995 .

[55]  Norman L. Allinger,et al.  Molecular mechanics. The MM3 force field for hydrocarbons. 1 , 1989 .