title: Assessment of QM/MM scoring functions for molecular docking to HIV-1 protease.
abstract: We explore the ability of four quantum mechanical (QM)/molecular mechanical (MM) models to accurately identify the native pose of six HIV-1 protease inhibitors and compare them with the AMBER force field and ChemScore and GoldScore scoring functions. Three QM/MM scoring functions treated the ligand at the HF/6-31G*, AM1d, and PM3 levels; the fourth QM/MM function modeled the ligand and active site at the PM3-D level. For the discrimination of native from non-native poses, solvent-corrected HF/6-31G*:AMBER and AMBER functions exhibited the best overall performance. While the electrostatic component of the MM and QM/MM functions appears important for discriminating the native pose of the ligand, the polarization contribution in the QM/MM functions was relatively insensitive to a ligand's binding mode and, for one ligand, actually hindered discrimination. The inclusion of a desolvation penalty, here using a generalized Born solvent model, improved discrimination for the MM and QM/MM methods. There appeared to be no advantage to binding mode prediction by incorporating active site polarization at the PM3-D level. Finally, we found that choice of the protonation state of the aspartyl dyad in the HIV-1 protease active site influenced the ability of scoring methods to determine the native binding pose.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences and School of Chemistry, University of Manchester, Oxford Road, Manchester, M13 9PT, United Kingdom.
authors.forename: Pedro
authors.initials: P
authors.lastname: Fong
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: McNamara
authors.forename: Ian H
authors.initials: IH
authors.lastname: Hillier
authors.forename: Richard A
authors.initials: RA
authors.lastname: Bryce
mesh_terms: D000465:Algorithms; D020134:Catalytic Domain; D016333:HIV Protease / Q000737:chemistry*; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D015497:HIV-1 / Q000201:enzymology*; D008958:Models, Molecular; D011789:Quantum Theory; D013329:Structure-Activity Relationship
chemical_list: D017320:HIV Protease Inhibitors; D016333:HIV Protease