Hybrid quantum mechanical/molecular mechanical molecular dynamics simulations of HIV-1 integrase/inhibitor complexes.

Human immunodeficiency virus (HIV)-1 integrase (IN) is an attractive target for development of acquired immunodeficiency syndrome chemotherapy. In this study, conventional and coupled quantum mechanical and molecular mechanical (QM/MM) molecular dynamics (MD) simulations of HIV-1 IN complexed with 5CITEP (IN-5CITEP) were carried out. In addition to differences in the bound position of 5CITEP, significant differences at the two levels of theory were observed in the metal coordination geometry and the areas involving residues 116-119 and 140-166. In the conventional MD simulation, the coordination of Mg(2+) was found to be a near-perfect octahedral geometry whereas a distorted octahedral complex was observed in QM/MM. All of the above reasons lead to a different pattern of protein-ligand salt link formation that was not observed in the classical MD simulation. Furthermore to provide a theoretical understanding of inhibition mechanisms of 5CITEP and its derivative (DKA), hybrid QM/MM MD simulations of the two complexes (IN-5CITEP and IN-DKA) have been performed. The results reveal that areas involving residues 60-68, 116-119, and 140-149 were substantially different among the two systems. The two systems show similar pattern of metal coordination geometry, i.e., a distorted octahedron. In IN-DKA, both OD1 and OD2 of Asp-64 coordinate the Mg(2+) in a monodentate fashion whereas only OD1 is chelated to the metal as observed in IN-5CITEP. The high potency of DKA as compared to 5CITEP is supported by a strong salt link formed between its carboxylate moiety and the ammonium group of Lys-159. Detailed comparisons between HIV-1 IN complexed with DKA and with 5CITEP provide information about ligand structure effects on protein-ligand interactions in particular with the Lys-159. This is useful for the design of new selective HIV-1 IN inhibitors.