title: Calculating binding free energies of host-guest systems using the AMOEBA polarizable force field.
abstract: Molecular recognition is of paramount interest in many applications. Here we investigate a series of host-guest systems previously used in the SAMPL4 blind challenge by using molecular simulations and the AMOEBA polarizable force field. The free energy results computed by Bennett's acceptance ratio (BAR) method using the AMOEBA polarizable force field ranked favorably among the entries submitted to the SAMPL4 host-guest competition [Muddana, et al., J. Comput.-Aided Mol. Des., 2014, 28, 305-317]. In this work we conduct an in-depth analysis of the AMOEBA force field host-guest binding thermodynamics by using both BAR and the orthogonal space random walk (OSRW) methods. The binding entropy-enthalpy contributions are analyzed for each host-guest system. For systems of inordinate binding entropy-enthalpy values, we further examine the hydrogen bonding patterns and configurational entropy contribution. The binding mechanism of this series of host-guest systems varies from ligand to ligand, driven by enthalpy and/or entropy changes. Convergence of BAR and OSRW binding free energy methods is discussed. Ultimately, this work illustrates the value of molecular modelling and advanced force fields for the exploration and interpretation of binding thermodynamics.
authors.affiliation: Department of Biomedical Engineering, The University of Texas at Austin, Austin, Texas 78712, United States.
authors.forename: David R
authors.initials: DR
authors.lastname: Bell
authors.affiliation: Department of Biomedical Engineering, The University of Texas at Austin, Austin, Texas 78712, United States.
authors.forename: Rui
authors.initials: R
authors.lastname: Qi
authors.affiliation: Department of Biomedical Engineering, The University of Texas at Austin, Austin, Texas 78712, United States.
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Jing
authors.affiliation: Computational and Molecular Biophysics Program, Washington Univ. School of Medicine, Saint Louis, Missouri 63130, United States.
authors.forename: Jin Yu
authors.initials: JY
authors.lastname: Xiang
authors.affiliation: Department of Chemistry, Washington University in Saint Louis, Saint Louis, Missouri 63130, United States.
authors.forename: Christopher
authors.initials: C
authors.lastname: Mejias
authors.affiliation: Department of Biomedical Engineering and Department of Biochemistry, University of Iowa, Iowa City, Iowa 52242, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Schnieders
authors.affiliation: Department of Chemistry, Washington University in Saint Louis, Saint Louis, Missouri 63130, United States.
authors.forename: Jay W
authors.initials: JW
authors.lastname: Ponder
authors.affiliation: Department of Biomedical Engineering, The University of Texas at Austin, Austin, Texas 78712, United States.
authors.forename: Pengyu
authors.initials: P
authors.lastname: Ren