Structure and dynamic of HIV-1 Integrase : molecular modeling and molecular dynamics simulations

Abstract

The complete full-length structure of HIV-1 integrase, a promising target for the design of anti-AIDS drugs, was theoretically modeled from experimental data of its fragments. The two experimental structures of two-domain fragment were used to carefully build the reliable full-length structure, particularly the linkages between core and N-terminal domains (CORE-N), and core and C-terminal domains (CORE-C). 2-ns molecular dynamics simulations were performed for the full-length HIV-1 integrase model in two cases, namely with and without a Mg2+ ion in the active site of the catalytic core domain. The structural and dynamical properties of the one-domain fragment, CORE, and the two-domain fragments, CORE-N and CORE-C, were also calculated in order to investigate effect of the terminal end on the catalytic core domain. The results show high flexibility in the experimentally missing region of the HIV-1 structure in all cases. Among the three domains, the C-terminal has the largest flexibility. Such flexibility was supposed to facilitate in the DNA binding process during the integration reaction. The metal ion has significant effects on the orientation and conformation of key residues in the active site as indicated by substantial changes in the distances and angles between the residues and ion in the active site region. A dimer and tetramer full-length HIV-1 IN complexed with DNA was successfully modeled herein based on the available experimental data.