Assessment of QM/MM scoring functions for molecular docking to HIV-1 protease

Pedro Fong, Jonathan P. McNamara, Ian H. Hillier, Richard A. Bryce

Research output: Contribution to journalArticlepeer-review

46 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)913-924
Number of pages12
JournalJournal of Chemical Information and Modeling
Issue number4
Publication statusPublished - 27 Apr 2009
Externally publishedYes


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