title: Parameterization of an effective potential for protein-ligand binding from host-guest affinity data.
abstract: Force field accuracy is still one of the "stalemates" in biomolecular modeling. Model systems with high quality experimental data are valuable instruments for the validation and improvement of effective potentials. With respect to protein-ligand binding, organic host-guest complexes have long served as models for both experimental and computational studies because of the abundance of binding affinity data available for such systems. Binding affinity data collected for cyclodextrin (CD) inclusion complexes, a popular model for molecular recognition, is potentially a more reliable resource for tuning energy parameters than hydration free energy measurements. Convergence of binding free energy calculations on CD host-guest systems can also be obtained rapidly, thus offering the opportunity to assess the robustness of these parameters. In this work, we demonstrate how implicit solvent parameters can be developed using binding affinity experimental data and the binding energy distribution analysis method (BEDAM) and validated using the Grid Inhomogeneous Solvation Theory analysis. These new solvation parameters were used to study protein-ligand binding in two drug targets against the HIV-1 virus and improved the agreement between the calculated and the experimental binding affinities. This work illustrates how benchmark sets of high quality experimental binding affinity data and physics-based binding free energy models can be used to evaluate and optimize force fields for protein-ligand systems. Copyright © 2015 John Wiley & Sons, Ltd.
authors.affiliation: Borough of Manhattan Community College, Department of Science, The City University of New York, New York, NY, 10007, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Wickstrom
authors.affiliation: Center for Biophysics and Computational Biology/ICMS, Department of Chemistry, Temple University, Philadelphia, PA, 19122, USA.
authors.forename: Nanjie
authors.initials: N
authors.lastname: Deng
authors.affiliation: Center for Biophysics and Computational Biology/ICMS, Department of Chemistry, Temple University, Philadelphia, PA, 19122, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: He
authors.affiliation: Center for Biophysics and Computational Biology/ICMS, Department of Chemistry, Temple University, Philadelphia, PA, 19122, USA.
authors.forename: Ahmet
authors.initials: A
authors.lastname: Mentes
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, 92093-0736, USA.
authors.forename: Crystal
authors.initials: C
authors.lastname: Nguyen
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, 92093-0736, USA.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Gilson
authors.affiliation: Department of Chemistry, Lehman College, The City University of New York, Bronx, NY, 10468, USA.
authors.forename: Tom
authors.initials: T
authors.lastname: Kurtzman
authors.affiliation: Department of Chemistry, Brooklyn College, The City University of New York, Brooklyn, NY, 11210, USA.
authors.forename: Emilio
authors.initials: E
authors.lastname: Gallicchio
authors.affiliation: Center for Biophysics and Computational Biology/ICMS, Department of Chemistry, Temple University, Philadelphia, PA, 19122, USA.
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Levy
mesh_terms: D019427:HIV Integrase / Q000737:chemistry / Q000378:metabolism*; D016333:HIV Protease / Q000737:chemistry / Q000378:metabolism*; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D013816:Thermodynamics; D047392:beta-Cyclodextrins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D008024:Ligands; D047392:beta-Cyclodextrins; D019427:HIV Integrase; D016333:HIV Protease
keywords: BEDAM; GIST; OPLS; force field; free energy