title: Thermodynamic integration to predict host-guest binding affinities.
abstract: An alchemical free energy method with explicit solvent molecular dynamics simulations was applied as part of the blind prediction contest SAMPL3 to calculate binding free energies for seven guests to an acyclic cucurbit-[n]uril host. The predictions included determination of protonation states for both host and guests, docking pose generation, and binding free energy calculations using thermodynamic integration. We found a root mean square error (RMSE) of 3.6 kcal mol(-1) from the reference experimental results, with an R(2) correlation of 0.51. The agreement with experiment for the largest contributor to this error, guest 6, is improved by 1.7 kcal mol(-1) when a periodicity-induced free energy correction is applied. The corrections for the other ligands were significantly smaller, and altogether the RMSE was reduced by 0.4 kcal mol(-1). We link properties of the host-guest systems during simulation to errors in the computed free energies. Overall, we show that charged host-guest systems studied here, initialized in unconfirmed docking poses, present a challenge to accurate alchemical simulation methods.
authors.affiliation: Department of Chemistry and Biochemistry, Center for Theoretical Biological Physics, University of California, San Diego, La Jolla, CA, USA. mlawrenz@ucsd.edu
authors.forename: Morgan
authors.initials: M
authors.lastname: Lawrenz
authors.forename: Jeff
authors.initials: J
authors.lastname: Wereszczynski
authors.forename: Juan Manuel
authors.initials: JM
authors.lastname: Ortiz-Sánchez
authors.forename: Sara E
authors.initials: SE
authors.lastname: Nichols
authors.forename: J Andrew
authors.initials: JA
authors.lastname: McCammon
mesh_terms: D001952:Bridged-Ring Compounds / Q000737:chemistry; D018360:Crystallography, X-Ray; D007093:Imidazoles / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D011485:Protein Binding; D013816:Thermodynamics; D047028:Macrocyclic Compounds; D000099246:Cucurbit(n)urils
chemical_list: D001952:Bridged-Ring Compounds; D007093:Imidazoles; D008024:Ligands; C523802:cucurbit(5)uril; D047028:Macrocyclic Compounds; D000099246:Cucurbit(n)urils