title: Calculation of absolute ligand binding free energy to a ribosome-targeting protein as a function of solvent model.
abstract: A comparative analysis is provided of the effect of different solvent models on the calculation of a potential of mean force (PMF) for determining the absolute binding affinity of the small molecule inhibitor pteroic acid bound to ricin toxin A-chain (RTA). Solvent models include the distance-dependent dielectric constant, several different generalized Born (GB) approximations, and a hybrid explicit/GB-based implicit solvent model. We found that the simpler approximation of dielectric screening and a GB model, with Born radii fitted to a switching-window dielectric-boundary surface Poisson solvent model, severely overpredicted the binding affinity as compared to the experimental value, estimated to range from -4.4 to -6.0 kcal/mol. In contrast, GB models that are parametrized to fit the Lee-Richards molecular surface performed much better, predicting binding free energy within 1-3 kcal/mol of experimental estimates. However, the predicted free-energy profiles of these GB models displayed alternative binding modes not observed in the crystal structure. Finally, the most rigorous and computationally costly approach in this work, which used a hybrid explicit/implicit solvent model, correctly determined a binding funnel in the PMF near the crystallographic bound state and predicted an absolute binding affinity that was 2 kcal/mol more favorable than the estimated experimental binding affinity.
authors.affiliation: Computational Sciences and Engineering Branch, U.S. Army Research Laboratory, Aberdeen Proving Ground, Maryland 21005, USA. michael.lee@amedd.army.mil
authors.forename: Michael S
authors.initials: MS
authors.lastname: Lee
authors.forename: Mark A
authors.initials: MA
authors.lastname: Olson
mesh_terms: D019295:Computational Biology; D008024:Ligands; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D011622:Pterins / Q000737:chemistry* / Q000494:pharmacology; D012276:Ricin / Q000037:antagonists & inhibitors / Q000737:chemistry*; D012997:Solvents / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D008024:Ligands; D011622:Pterins; D012997:Solvents; C005584:pteroic acid; D012276:Ricin