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

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 π-π stacking interactions are important, the combined effect of a number of C-H/π 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. © 2010 the Owner Societies.