A QM/MM study of the reaction mechanism for the 3′-processing step catalyzed by HIV-1 integrase

Abstract

Integrase (IN) is one of the three human immunodeficiency virus type 1 enzymes (HIV-1) essential for effective viral replication. This viral enzyme is involved in the integration of HIV DNA into host chromosomal DNA. In this work we have carried out molecular dynamics simulations using a hybrid Quantum Mechanics/Molecular Mechanics (QM/MM) approach to study the reaction mechanism for the 3′-processing step of DNA integration using a model substrate. The results obtained by QM(AM1)/MM and QM(PM3)/MM simulations have been improved by single-point corrections using an ab initio method to describe the quantum subsystem. The results obtained within this computational model can be used to obtain a good approach to the actual chemical mechanism used by the enzyme to catalyze the reaction with DNA and which are the most important substrate-protein interactions along the chemical reaction progress. © 2008 Elsevier B.V. All rights reserved.