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 Å. 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. Proteins 2005. © 2005 Wiley‐Liss, Inc.

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