title: Prediction of Absolute Solvation Free Energies using Molecular Dynamics Free Energy Perturbation and the OPLS Force Field.
abstract: The accurate prediction of protein-ligand binding free energies is a primary objective in computer-aided drug design. The solvation free energy of a small molecule provides a surrogate to the desolvation of the ligand in the thermodynamic process of protein-ligand binding. Here, we use explicit solvent molecular dynamics free energy perturbation to predict the absolute solvation free energies of a set of 239 small molecules, spanning diverse chemical functional groups commonly found in drugs and drug-like molecules. We also compare the performance of absolute solvation free energies obtained using the OPLS_2005 force field with two other commonly used small molecule force fields-general AMBER force field (GAFF) with AM1-BCC charges and CHARMm-MSI with CHelpG charges. Using the OPLS_2005 force field, we obtain high correlation with experimental solvation free energies (R(2) = 0.94) and low average unsigned errors for a majority of the functional groups compared to AM1-BCC/GAFF or CHelpG/CHARMm-MSI. However, OPLS_2005 has errors of over 1.3 kcal/mol for certain classes of polar compounds. We show that predictions on these compound classes can be improved by using a semiempirical charge assignment method with an implicit bond charge correction.
authors.affiliation: Schrödinger, Inc., 120 West 45th Street, 17th Floor, New York, New York 10036 and 101 SW Main Street, Suite 1300, Portland, Oregon 97204.
authors.forename: Devleena
authors.initials: D
authors.lastname: Shivakumar
authors.affiliation: Schrödinger, Inc., 120 West 45th Street, 17th Floor, New York, New York 10036 and 101 SW Main Street, Suite 1300, Portland, Oregon 97204.
authors.forename: Joshua
authors.initials: J
authors.lastname: Williams
authors.affiliation: Schrödinger, Inc., 120 West 45th Street, 17th Floor, New York, New York 10036 and 101 SW Main Street, Suite 1300, Portland, Oregon 97204.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Schrödinger, Inc., 120 West 45th Street, 17th Floor, New York, New York 10036 and 101 SW Main Street, Suite 1300, Portland, Oregon 97204.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Damm
authors.affiliation: Schrödinger, Inc., 120 West 45th Street, 17th Floor, New York, New York 10036 and 101 SW Main Street, Suite 1300, Portland, Oregon 97204.
authors.forename: John
authors.initials: J
authors.lastname: Shelley
authors.affiliation: Schrödinger, Inc., 120 West 45th Street, 17th Floor, New York, New York 10036 and 101 SW Main Street, Suite 1300, Portland, Oregon 97204.
authors.forename: Woody
authors.initials: W
authors.lastname: Sherman