title: Calculating protein-ligand binding affinities with MMPBSA: Method and error analysis.
abstract: Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) methods have become widely adopted in estimating protein-ligand binding affinities due to their efficiency and high correlation with experiment. Here different computational alternatives were investigated to assess their impact to the agreement of MMPBSA calculations with experiment. Seven receptor families with both high-quality crystal structures and binding affinities were selected. First the performance of nonpolar solvation models was studied and it was found that the modern approach that separately models hydrophobic and dispersion interactions dramatically reduces RMSD's of computed relative binding affinities. The numerical setup of the Poisson-Boltzmann methods was analyzed next. The data shows that the impact of grid spacing to the quality of MMPBSA calculations is small: the numerical error at the grid spacing of 0.5 Å is already small enough to be negligible. The impact of different atomic radius sets and different molecular surface definitions was further analyzed and weak influences were found on the agreement with experiment. The influence of solute dielectric constant was also analyzed: a higher dielectric constant generally improves the overall agreement with experiment, especially for highly charged binding pockets. The data also showed that the converged simulations caused slight reduction in the agreement with experiment. Finally the direction of estimating absolute binding free energies was briefly explored. Upon correction of the binding-induced rearrangement free energy and the binding entropy lost, the errors in absolute binding affinities were also reduced dramatically when the modern nonpolar solvent model was used, although further developments were apparently necessary to further improve the MMPBSA methods. © 2016 Wiley Periodicals, Inc.
authors: Chemical and Materials Physics Graduate Program, Irvine, California, 92697.|Department of Molecular Biology and Biochemistry, Irvine, California, 92697.|Department of Physics and Astronomy, University of California, Irvine, California, 92697.
authors: Changhao
authors: C
authors: Wang
authors: Department of Molecular Biology and Biochemistry, Irvine, California, 92697.
authors: Peter H
authors: PH
authors: Nguyen
authors: Department of Molecular Biology and Biochemistry, Irvine, California, 92697.
authors: Kevin
authors: K
authors: Pham
authors: Department of Molecular Biology and Biochemistry, Irvine, California, 92697.
authors: Danielle
authors: D
authors: Huynh
authors: Department of Molecular Biology and Biochemistry, Irvine, California, 92697.
authors: Thanh-Binh Nancy
authors: TB
authors: Le
authors: Department of Molecular Biology and Biochemistry, Irvine, California, 92697.
authors: Hongli
authors: H
authors: Wang
authors: Department of Biomedical Engineering, University of Texas, Austin, Texas, 78712.
authors: Pengyu
authors: P
authors: Ren
authors: Chemical and Materials Physics Graduate Program, Irvine, California, 92697. rluo@uci.edu.|Department of Molecular Biology and Biochemistry, Irvine, California, 92697. rluo@uci.edu.|Department of Chemical Engineering and Materials Science, Irvine, California, 92697. rluo@uci.edu.|Department of Biomedical Engineering, University of California, Irvine, California, 92697. rluo@uci.edu.
authors: Ray
authors: R
authors: Luo
mesh_terms: D008024:Ligands; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry*; D012997:Solvents / Q000737:chemistry; D013499:Surface Properties; D013816:Thermodynamics
chemical_list: D008024:Ligands; D011506:Proteins; D012997:Solvents
keywords: Poisson-Boltzmann implicit solvent models; molecular dynamics; nonpolar solvent models