A study of the binding energies of efavirenz to wild-type and K103N/Y181C HIV-1 reverse transcriptase based on the ONIOM method.

A three-layered ONIOM model was used to study the interactions between efavirenz and the binding sites of HIV-1 reverse transcriptase (RT): wild-type and double mutant K103N/Y181C enzyme forms. Binding energies were determined and compared to describe the loss of activity of efavirenz with the mutant HIV-1 RT binding pocket. The calculated binding energy for the efavirenz-K103N/Y181C HIV-1 RT complex is less than that with the wild-type complex by approximately 8 kcal mol(-1). The interaction energies, calculated at the MP2/6-31G(d,p) level between efavirenz and individual residues surrounding the binding pocket of the K103N/Y181C enzyme, demonstrate that the attractive interactions between efavirenz and residue positions 101 and 103 were less than those for wild-type RT by 5.52 and 3.62 kcal mol(-1), respectively. Understanding these interactions could be useful in the design of inhibitors specific for the HIV-1 RT allosteric site and that have greater potency against the mutant enzyme.