title: A quantum mechanic/molecular mechanic study of the wild-type and N155S mutant HIV-1 integrase complexed with diketo acid.
abstract: Integrase (IN) is one of the three human immunodeficiency virus type 1 (HIV-1) enzymes essential for effective viral replication. Recently, mutation studies have been reported that have shown that a certain degree of viral resistance to diketo acids (DKAs) appears when some amino acid residues of the IN active site are mutated. Mutations represent a fascinating experimental challenge, and we invite theoretical simulations for the disclosure of still unexplored features of enzyme reactions. The aim of this work is to understand the molecular mechanisms of HIV-1 IN drug resistance, which will be useful for designing anti-HIV inhibitors with unique resistance profiles. In this study, we use molecular dynamics simulations, within the hybrid quantum mechanics/molecular mechanics (QM/MM) approach, to determine the protein-ligand interaction energy for wild-type and N155S mutant HIV-1 IN, both complexed with a DKA. This hybrid methodology has the advantage of the inclusion of quantum effects such as ligand polarization upon binding, which can be very important when highly polarizable groups are embedded in anisotropic environments, for example in metal-containing active sites. Furthermore, an energy terms decomposition analysis was performed to determine contributions of individual residues to the enzyme-inhibitor interactions. The results reveal that there is a strong interaction between the Lys-159, Lys-156, and Asn-155 residues and Mg(2+) cation and the DKA inhibitor. Our calculations show that the binding energy is higher in wild-type than in the N155S mutant, in accordance with the experimental results. The role of the mutated residue has thus been checked as maintaining the structure of the ternary complex formed by the protein, the Mg(2+) cation, and the inhibitor. These results might be useful to design compounds with more interesting anti-HIV-1 IN activity on the basis of its three-dimensional structure.
authors.affiliation: Laboratório de Planejamento e Desenvolvimento de Fármacos, Instituto de Ciências Exatas e Naturais, Universidade Federal do Pará, CP 11101, 66075-110 Belém, PA, Brazil. nahum@ufpa.br
authors.forename: Cláudio Nahum
authors.initials: CN
authors.lastname: Alves
authors.forename: Sergio
authors.initials: S
authors.lastname: Martí
authors.forename: Raquel
authors.initials: R
authors.lastname: Castillo
authors.forename: Juan
authors.initials: J
authors.lastname: Andrés
authors.forename: Vicent
authors.initials: V
authors.lastname: Moliner
authors.forename: Iñaki
authors.initials: I
authors.lastname: Tuñón
authors.forename: Estanislao
authors.initials: E
authors.lastname: Silla
mesh_terms: D000613:Aminobutyrates / Q000737:chemistry*; D001665:Binding Sites; D003198:Computer Simulation; D019427:HIV Integrase / Q000737:chemistry* / Q000235:genetics / Q000648:ultrastructure*; D019429:Integrase Inhibitors / Q000737:chemistry*; D008274:Magnesium / Q000737:chemistry; D019563:Mechanics; D008956:Models, Chemical; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000737:chemistry / Q000648:ultrastructure; D016297:Mutagenesis, Site-Directed; D010654:Phenylbutyrates; D011485:Protein Binding; D011487:Protein Conformation; D011789:Quantum Theory
chemical_list: C515357:2,4-dioxo-4-phenylbutanoic acid; D000613:Aminobutyrates; D019429:Integrase Inhibitors; D046912:Multiprotein Complexes; D010654:Phenylbutyrates; D019427:HIV Integrase; D008274:Magnesium; C514801:p31 integrase protein, Human immunodeficiency virus 1