Prediction of Absolute Solvation Free Energies using Molecular Dynamics Free Energy Perturbation and the OPLS Force Field
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- 作者：Devleena Shivakumar ; Joshua Williams ; Yujie Wu ; Wolfgang Damm ; John Shelley ; Woody Sherman
- 刊名：Journal of Chemical Theory and Computation
- 出版年：2010
- 出版时间：May 11, 2010
- 年：2010
- 卷：6
- 期：5
- 页码：1509-1519
- 全文大小：279K
- 年卷期：v.6,no.5(May 11, 2010)
- ISSN：1549-9626
文摘
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 (R2 = 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.