title: Protein/ligand binding free energies calculated with quantum mechanics/molecular mechanics.
abstract: The calculation of binding affinities for flexible ligands has hitherto required the availability of reliable molecular mechanics parameters for the ligands, a restriction that can in principle be lifted by using a mixed quantum mechanics/molecular mechanics (QM/MM) representation in which the ligand is treated quantum mechanically. The feasibility of this approach is evaluated here, combining QM/MM with the Poisson-Boltzmann/surface area model of continuum solvation and testing the method on a set of 47 benzamidine derivatives binding to trypsin. The experimental range of the absolute binding energy (DeltaG = -3.9 to -7.6 kcal/mol) is reproduced well, with a root-mean-square (RMS) error of 1.2 kcal/mol. When QM/MM is applied without reoptimization to the very different ligands of FK506 binding protein the RMS error is only 0.7 kcal/mol. The results show that QM/MM is a promising new avenue for automated docking and scoring of flexible ligands. Suggestions are made for further improvements in accuracy.
authors.affiliation: IWR--Computational Biochemistry, University of Heidelberg, Im Neuenheimer Feld 368, 69120 Heidelberg, Germany.
authors.forename: Frauke
authors.initials: F
authors.lastname: Gräter
authors.forename: Sonja M
authors.initials: SM
authors.lastname: Schwarzl
authors.forename: Annick
authors.initials: A
authors.lastname: Dejaegere
authors.forename: Stefan
authors.initials: S
authors.lastname: Fischer
authors.forename: Jeremy C
authors.initials: JC
authors.lastname: Smith
mesh_terms: D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D011789:Quantum Theory
chemical_list: D008024:Ligands