Structures and energetics of darunavir and active site amino acids of native and mutant HIV–1 protease: a computational study

Quantum chemical calculations have been performed at the M06–2X/6–31G(d,p) level of theory to investigate the strength and nature of interactions between the active site amino acids at positions 25 and 30 with darunavir (DRV) inhibitor of two native (D25 and D30 in 4LL3, 1T3R) and five mutant (N25 in 3BVB, 3SO9; N30 in 2F80, 3LZV, 3UCB) HIV–1 proteases. Molecular orbitals HOMO and LUMO noted down upon the M06–2X/6–31G(d,p) level optimized amino acid–DRV geometries helped us explain which region of the inhibitor has the ability to interact with the amino acid more effectively. This analysis of the molecular orbitals allowed us to explore the nature of the interactions present between active site amino acids and the DRV in native and mutated proteins. The electrostatic potential surface maps generated for the amino acid–DRV complexes investigated the extent of interactions within the active site of the protein. Natural bond order analysis performed on the optimized geometries suggested that the extent of charge transfer helps in determining the stability of the complexes, which is very important for drug design.