title: Modelling the binding of HIV-reverse transcriptase and nevirapine: an assessment of quantum mechanical and force field approaches and predictions of the effect of mutations on binding.
abstract: The importance of the intermolecular interactions which contribute to the binding of HIV-1 RT with the NNRTI inhibitor, nevirapine (NVP), has been studied using quantum mechanical and molecular simulation methods. A range of computational methods, including density functional theory with empirical dispersion corrections, have been employed and show that although pi-pi stacking interactions are important, the combined effect of a number of C-H/pi interactions provides a significant contribution to the binding. The AMBER empirical force-field has been shown to be particularly effective to describe the interactions in this case; MM-GBSA free-energy methods were subsequently used to explore the effects on binding with several known mutations of HIV-1 RT. The relative affinities from the mutation simulations are shown to be in good agreement with experimental data allowing the causes of the binding changes to be discussed.
authors.affiliation: School of Chemistry, University of Manchester, Manchester, UK.
authors.forename: Rajesh K
authors.initials: RK
authors.lastname: Raju
authors.forename: Neil A
authors.initials: NA
authors.lastname: Burton
authors.forename: Ian H
authors.initials: IH
authors.lastname: Hillier
mesh_terms: D019943:Amino Acid Substitution; D019380:Anti-HIV Agents / Q000737:chemistry*; D001665:Binding Sites; D054303:HIV Reverse Transcriptase / Q000737:chemistry* / Q000235:genetics; D056004:Molecular Dynamics Simulation; D009154:Mutation; D019829:Nevirapine / Q000737:chemistry*; D011485:Protein Binding; D011789:Quantum Theory; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D019829:Nevirapine; D054303:HIV Reverse Transcriptase