Binding energy analysis for wild-type and Y181C mutant HIV-1 RT/8-Cl TIBO complex structures: quantum chemical calculations based on the ONIOM method.

Two-layered and three-layered ONIOM calculations were performed to compare the binding energies of 8-Cl TIBO inhibitor when bound into the human immunodeficiency virus reverse transcriptase binding pocket and a Y181C variant. Both consisted of 20 residues within a radius of 15 A. A combination of different methods [MP2/6-31G(d), B3LYP/6-31G(d,p), and PM3] were performed to take advantage of ONIOM's layering strategy analysis. The obtained results clearly indicate that the Y181C mutation reduces the binding affinity and stability of the inhibitor by approximately 8-9 kcal/mol as obtained from different combined MO:MO methods. Analyses regarding the energetic components of the interaction and deformation energies for 8-Cl TIBO inhibitor upon binding were also examined extensively. Additional calculations involving the interaction energies between 8-Cl TIBO with individual residues surrounding the binding pocket were performed at MP2/6-31G(d,p) and B3LYP/6-31G(d,p) levels of theory to gain more insight into the energetic differences of wild-type and Y181C mutant type at the atomistic level.