Similarities in the HIV-1 and ASV integrase active sites upon metal cofactor binding

The HIV-1 integrase, which is essential for viral replication, catalyzes th e insertion of viral DNA into the host chromosome thereby recruiting host c ell machinery into making viral proteins. It represents the third main HN e nzyme target for inhibitor design, the first two being the reverse transcri ptase and the protease. We report here a fully hydrated 2 ns molecular dyna mics simulation performed using parallel NWChem3.2.1 with the AMBER95 force field. The HIV-1 integrase catalytic domain previously determined by cryst allography (IB9D) and modeling including two Mg2+ ions placed into the acti ve site based on an alignment against an ASV integrase structure containing two divalent metals (1VSH), was used as the starting structure. The simula tion reveals a high degree of flexibility in the region of residues 140-149 even in the presence of a second divalent metal ion and a dramatic conform ational change of the side chain of E152 when the second metal ion is prese nt. This study shows similarities in the behavior of the catalytic residues in the HIV-1 and ASV integrases upon metal binding. The present simulation also provides support to the hypothesis that the second metal ion is likel y to be carried into the HIV-1 integrase active site by the substrate, a st rand of DNA. (C) 2000 John Wiley & Sons, Inc. Biopoly 53: 308-315, 2000.