title: Computational studies of the interaction between the HIV-1 integrase tetramer and the cofactor LEDGF/p75: insights from molecular dynamics simulations and the informational spectrum method.
abstract: A crystal structure of the integrase binding domain (IBD) of the lens epithelium-derived growth factor (LEDGF/p75) in complex with the dimer of the HIV-1 integrase (IN) catalytic core domain (CCD) provides useful information that might help in the understanding of essential protein-protein contacts in HIV-1. However, mutagenic studies indicated that interactions between the full-length proteins were more extensive than the contacts observed in the co-crystal structure of the isolated domains. On the other hand, the biochemical characterization of the interaction between full-length IN and LEDGF/p75 has recently proved that LEDGF/p75 promotes IN tetramerization with two LEDGF/p75 IBD molecules bound to the IN tetramer. This experimental evidence suggests that to obtain a complete structural description of the interactions between the two proteins, the full-length tetrameric structure of IN should be considered. Our aim was to obtain a detailed picture of HIV-1 IN interactions with cellular co-factors that was of general interest, particularly for the development of small molecule IN inhibitors, which mimic the IBD of LEDGF/p75. To this end, we performed bioinformatics analyses to identify protein sequence domains involved in long-range recognition. Subsequently, we applied molecular dynamics techniques to investigate the detailed interactions between the complete tetrameric form of IN and two molecules of the IBD of LEDGF/p75. Our dynamic picture is in agreement with experimental data and, thereby, provides new details of the IN-LEDGF/p75 interaction.
authors.affiliation: Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via Alcide de Gasperi 2, I-53100 Siena, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Tintori
authors.forename: Nevena
authors.initials: N
authors.lastname: Veljkovic
authors.forename: Veljko
authors.initials: V
authors.lastname: Veljkovic
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
mesh_terms: D019295:Computational Biology / Q000379:methods*; D019427:HIV Integrase / Q000737:chemistry* / Q000378:metabolism*; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D020539:Sequence Analysis, Protein / Q000379:methods*; D055672:Static Electricity; D013816:Thermodynamics; D013997:Time Factors
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; C119380:lens epithelium-derived growth factor; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1