title: Could MM-GBSA be accurate enough for calculation of absolute protein/ligand binding free energies?
abstract: Implicit solvation methods such as MM-GBSA, when applied to evaluating protein/ligand binding free energies, are widely believed to be accurate only for the estimation of relative binding free energies for a congeneric series of ligands. In this work, we show that the MM-GBSA flavor of Prime 3.0, VSGB-2.0, with a variable dielectric model and a novel energy function, could be approaching the accuracy required for evaluating absolute binding free energies, albeit, through a linear regression fit. The data-set used for validation includes 106 protein-ligand complexes that were carefully selected to control for variability in the affinity data as well as error in the modeled complexes. Through systematic analysis, we also quantify the degradation in the R(2) of fit between experimental and calculated values with either greater variability in the affinity data or an increase in error in the modeled protein/ligand complexes. Limitations for its application in drug discovery are discussed along with the identification of areas for future development.
authors.affiliation: Jubilant Biosys Limited, #96, Industrial Suburb, 2nd Stage, Yeshwanthpur, Bangalore 560 022, India. Electronic address: chandrika_mulakala@jubilantbiosys.com.
authors.forename: Chandrika
authors.initials: C
authors.lastname: Mulakala
authors.forename: Vellarkad N
authors.initials: VN
authors.lastname: Viswanadhan
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases / Q000737:chemistry; D000449:Aldehyde Reductase / Q000737:chemistry; D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000737:chemistry; D002417:Cattle; D006801:Humans; D008024:Ligands; D016014:Linear Models; D062105:Molecular Docking Simulation; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry*; D012984:Software; D013816:Thermodynamics; D014357:Trypsin / Q000737:chemistry
chemical_list: D008024:Ligands; D011506:Proteins; D000449:Aldehyde Reductase; D064413:3-Phosphoinositide-Dependent Protein Kinases; C578562:PDPK1 protein, human; D053829:Amyloid Precursor Protein Secretases; D014357:Trypsin; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
keywords: Absolute binding free energy; BACE; Free energy of binding; GB; GBSA; Implicit solvation; MM; MM-GBSA; PDPK-1; Protein/ligand binding; SGB; SGB with hydrophobic term added to the non-polar surface area term; SGB-NP; SGB-NP with a variable dielectric formulation; VSGB-1.0; VSGB-1.0 with an improved energy function; VSGB-2.0; generalized-Born; generalized-Born surface area; molecular mechanics; phosphoinositide-dependent kinase-1; surface-area based generalized Born; β-secretase