An effective tripeptide inhibitor, 2-naphthoylLysLysArgH (Naph-KKR-H), acts as an inhibitor againstWest Nile Virus (WNV) NS3 protease (NS 3pro). Two conformations of Naph-KKR-H were found in the crystal structure of WNV NS2B cofactor and NS3pro. In this study, divide-and-conquer-based density functional theory and second-order MollerPlesset perturbation theory calculations were applied in order to clarify the binding mechanism of both conformations. The solvent effect was also examined. In addition, bond energy density analysis (BEDA) was performed to investigate the binding interaction. Interestingly, even though conformations 1 and 2 revealed the difference of interaction energies, energy barriers, reaction energies, and type of reaction, the energy differences of tetrahedral intermediate forms as compared to their separated systems were close to each other with the energy difference of ca. 4 kcalmol-1. These results clearly indicated why both conformations existed in the crystal structure. The bond energy also showed the important interaction to the amino acids and role of water molecules in the active site. Furthermore, according to the high correlation between the changes of bond distance and bond energy, it was found that the BEDA technique is useful to study the binding mechanism.
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