title: Substituent-modulated affinities of halobenzene derivatives to the HIV-1 integrase recognition site. Analyses of the interaction energies by parallel quantum chemical and polarizable molecular mechanics.
abstract: The C-X bond of halobenzenes (X = Cl, Br) has a dual character, its electron density being depleted in its prolongation and built-up on its sides. We have recently considered three protein or nucleic acid recognition sites of halobenzenes and quantified the energy gains that either electron-attracting substituents or electron-donating ones contribute due to such a character (El Hage et al., paper in revision). Nonadditivity was found to impact the total interaction energies. We focus here on one recognition site, that of the HIV-1 integrase, in which the halobenzene ring of the drug elvitegravir is sandwiched between a guanine and a cytosine base. We perform energy-decomposition analyses of the ab initio quantum-chemistry (QC) binding energies of the parent halobenzene ring and its derivatives with this G-C base pair. In these complexes, the nonadditivity of ΔE could be traced back mostly to the polarization contribution Epol. In view of large-scale applications to the entirety of the complex formed between the integrase, the viral DNA, and the whole drug, the analyses were performed in parallel with a polarizable molecular mechanics method, SIBFA. This method could faithfully reproduce most features of the QC energies. This is due to its use of QC-derived distributed multipoles and polarizabilities, which enable us to account for both nonisotropy and nonadditivity.
authors.affiliation: Chemistry and Biology, Nucleo(s)tides and Immunology for Therapy (CBNIT), UMR 8601 CNRS, UFR Biomédicale , Paris 75006, France.
authors.forename: Krystel
authors.initials: K
authors.lastname: El Hage
authors.forename: Jean-Philip
authors.initials: JP
authors.lastname: Piquemal
authors.forename: Zeina
authors.initials: Z
authors.lastname: Hobaika
authors.forename: Richard G
authors.initials: RG
authors.lastname: Maroun
authors.forename: Nohad
authors.initials: N
authors.lastname: Gresh
mesh_terms: D001555:Benzene Derivatives / Q000737:chemistry*; D003198:Computer Simulation; D003596:Cytosine / Q000737:chemistry; D004247:DNA / Q000737:chemistry; D004583:Electrons; D006147:Guanine / Q000737:chemistry; D019427:HIV Integrase / Q000737:chemistry* / Q000235:genetics; D006860:Hydrogen Bonding; D008956:Models, Chemical; D008958:Models, Molecular; D011789:Quantum Theory; D015363:Quinolones / Q000737:chemistry*; D055672:Static Electricity
chemical_list: D001555:Benzene Derivatives; D015363:Quinolones; C509700:elvitegravir; D006147:Guanine; D003596:Cytosine; D004247:DNA; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1