title: Striking HIV-1 Entry by Targeting HIV-1 gp41. But, Where Should We Target?
abstract: HIV-1 gp41 facilitates the viral fusion through a conformational switch involving the association of three C-terminal helices along the conserved hydrophobic grooves of three N-terminal helices coiled-coil. The control of these structural rearrangements is thought to be central to HIV-1 entry and, therefore, different strategies of intervention are being developed. Herewith, we describe a procedure to simulate the folding of an HIV-1 gp41 simplified model. This procedure is based on the construction of plausible conformational pathways, which describe protein transition between non-fusogenic and fusogenic conformations. The calculation of the paths started with 100 molecular dynamics simulations of the non-fusogenic conformation, which were found to converge to different intermediate states. Those presenting defined criteria were selected for separate targeted molecular dynamics simulations, subjected to a force constant imposing a movement towards the gp41 fusogenic conformation. Despite significant diversity, a preferred sequence of events emerged when the simulations were analyzed in terms of the formation, breakage and evolution of the contacts. We pointed out 29 residues as the most relevant for the movement of gp41; also, 2696 possible interactions were reduced to only 48 major interactions, which reveals the efficiency of the method. The analysis of the evolution of the main interactions lead to the detection of four main behaviors for those contacts: stable, increasing, decreasing and repulsive interactions. Altogether, these results suggest a specific small cavity of the HIV-1 gp41 hydrophobic groove as the preferred target to small molecules.
authors.affiliation: Laboratoire Interfaces, Traitements, Organisation et Dynamique des Systèmes-ITODYS-Université Paris Diderot, Paris 7 -CNRS UMR 7086; 15 rue Jean Antoine de Baïf, 75205 Paris Cedex13, France.|CICECO-Instituto de Materiais de Aveiro, Departamento de Química, Universidade de Aveiro, Campus Universitário de Santiago, 3810-193 Aveiro, Portugal.|UCIBIO-REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências da Universidade do Porto, Rua do Campo Alegre 687, 4169-007 Porto, Portugal.
authors.forename: Cátia
authors.initials: C
authors.lastname: Teixeira
authors.affiliation: Laboratoire Interfaces, Traitements, Organisation et Dynamique des Systèmes-ITODYS-Université Paris Diderot, Paris 7 -CNRS UMR 7086; 15 rue Jean Antoine de Baïf, 75205 Paris Cedex13, France.
authors.forename: Florent
authors.initials: F
authors.lastname: Barbault
authors.affiliation: Laboratoire Interfaces, Traitements, Organisation et Dynamique des Systèmes-ITODYS-Université Paris Diderot, Paris 7 -CNRS UMR 7086; 15 rue Jean Antoine de Baïf, 75205 Paris Cedex13, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Couesnon
authors.affiliation: CICECO-Instituto de Materiais de Aveiro, Departamento de Química, Universidade de Aveiro, Campus Universitário de Santiago, 3810-193 Aveiro, Portugal.
authors.forename: José R B
authors.initials: JR
authors.lastname: Gomes
authors.affiliation: UCIBIO-REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências da Universidade do Porto, Rua do Campo Alegre 687, 4169-007 Porto, Portugal.
authors.forename: Paula
authors.initials: P
authors.lastname: Gomes
authors.affiliation: Laboratoire Interfaces, Traitements, Organisation et Dynamique des Systèmes-ITODYS-Université Paris Diderot, Paris 7 -CNRS UMR 7086; 15 rue Jean Antoine de Baïf, 75205 Paris Cedex13, France.
authors.forename: François
authors.initials: F
authors.lastname: Maurel
mesh_terms: D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000378:metabolism; D001665:Binding Sites; D015700:HIV Envelope Protein gp41 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D011485:Protein Binding; D017510:Protein Folding
chemical_list: D000998:Antiviral Agents; D015700:HIV Envelope Protein gp41