title: Toward Improved Force-Field Accuracy through Sensitivity Analysis of Host-Guest Binding Thermodynamics.
abstract: Improving the capability of atomistic computer models to predict the thermodynamics of noncovalent binding is critical for successful structure-based drug design, and the accuracy of such calculations remains limited by nonoptimal force field parameters. Ideally, one would incorporate protein-ligand affinity data into force field parametrization, but this would be inefficient and costly. We now demonstrate that sensitivity analysis can be used to efficiently tune Lennard-Jones parameters of aqueous host-guest systems for increasingly accurate calculations of binding enthalpy. These results highlight the promise of a comprehensive use of calorimetric host-guest binding data, along with existing validation data sets, to improve force field parameters for the simulation of noncovalent binding, with the ultimate goal of making protein-ligand modeling more accurate and hence speeding drug discovery.
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California 92093-0736, United States.
authors.forename: Jian
authors.initials: J
authors.lastname: Yin
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California 92093-0736, United States.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Fenley
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California 92093-0736, United States.
authors.forename: Niel M
authors.initials: NM
authors.lastname: Henriksen
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California 92093-0736, United States.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Gilson
mesh_terms: D001952:Bridged-Ring Compounds / Q000737:chemistry; D002151:Calorimetry; D015195:Drug Design; D007093:Imidazoles / Q000737:chemistry; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D012997:Solvents / Q000737:chemistry; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014867:Water / Q000737:chemistry; D047028:Macrocyclic Compounds; D000099246:Cucurbit(n)urils
chemical_list: D001952:Bridged-Ring Compounds; D007093:Imidazoles; D012997:Solvents; D014867:Water; C456276:cucurbit(7)uril; D047028:Macrocyclic Compounds; D000099246:Cucurbit(n)urils