title: Interactions of conformationally biased north and south 2'-fluoro-2', 3'-dideoxynucleoside 5'-triphosphates with the active site of HIV-1 reverse transcriptase.
abstract: Molecular dynamics simulations of a ternary complex of HIV-1 reverse transcriptase (RT), double-stranded DNA, and bound dideoxynucleoside-5'-triphosphate (RT-DNA-ddNTP), utilizing the ddNTPs ddATP, betaFddATP, and alphaFddATP, explain the experimentally observed order of potency of these 5'-triphosphates as inhibitors of RT: ddATP > betaFddATP > alphaFddATP. On the basis of RT's known preference to bind the incoming dNTP (or ddNTP) with a north conformation at the polymerase site, alphaFddATP, which in solution prefers almost exclusively a north conformation, was predicted to be the most potent inhibitor. However, Tyr115, which appears to function as a steric gate to preclude the binding of ribonucleoside 5'-triphosphates, prevents the effective binding of alphaFddATP in its preferred north conformation. The south-biased betaFddATP, while able to bind to RT without hindrance by Tyr115, has to pay a high energy penalty to be flipped to the active north conformation at the polymerase site. Finally, the more flexible and less conformationally biased ddATP is able to switch to a north conformation at the RT site with a smaller energy penalty than betaFddATP. These results highlight the opposite conformational preferences of HIV-1 RT for alphaFddATP and betaFddATP and help establish conformational guidelines for optimal binding at the polymerase site of this enzyme.
authors.affiliation: Laboratory of Medicinal Chemistry, Division of Basic Sciences, and Experimental Retrovirology Section, Medicine Branch, Division of Clinical Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: L
authors.initials: L
authors.lastname: Mu
authors.forename: S G
authors.initials: SG
authors.lastname: Sarafianos
authors.forename: M C
authors.initials: MC
authors.lastname: Nicklaus
authors.forename: P
authors.initials: P
authors.lastname: Russ
authors.forename: M A
authors.initials: MA
authors.lastname: Siddiqui
authors.forename: H
authors.initials: H
authors.lastname: Ford
authors.forename: H
authors.initials: H
authors.lastname: Mitsuya
authors.forename: R
authors.initials: R
authors.lastname: Le
authors.forename: E
authors.initials: E
authors.lastname: Kodama
authors.forename: C
authors.initials: C
authors.lastname: Meier
authors.forename: T
authors.initials: T
authors.lastname: Knispel
authors.forename: L
authors.initials: L
authors.lastname: Anderson
authors.forename: J J
authors.initials: JJ
authors.lastname: Barchi
authors.forename: V E
authors.initials: VE
authors.lastname: Marquez
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry; D001665:Binding Sites / Q000187:drug effects; D003838:Deoxyadenine Nucleotides / Q000737:chemistry* / Q000378:metabolism; D016048:Dideoxyadenosine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism; D054306:Dideoxynucleotides; D015226:Dinucleoside Phosphates / Q000737:chemistry; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008956:Models, Chemical; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D011487:Protein Conformation; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry; D013816:Thermodynamics; D014443:Tyrosine / Q000737:chemistry
chemical_list: D019380:Anti-HIV Agents; D003838:Deoxyadenine Nucleotides; D054306:Dideoxynucleotides; D015226:Dinucleoside Phosphates; D018894:Reverse Transcriptase Inhibitors; C037773:2',3'-dideoxyadenosine triphosphate; C073072:lodenosine; D014443:Tyrosine; D016048:Dideoxyadenosine; D054303:HIV Reverse Transcriptase