Interactions of conformationally biased north and south 2'-fluoro-2', 3'-dideoxynucleoside 5'-triphosphates with the active site of HIV-1 reverse transcriptase.
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.
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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.
Sarafianos
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Nicklaus
M C
MC
Russ
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Siddiqui
M A
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Ford
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Mitsuya
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H
Le
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R
Kodama
E
E
Meier
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Knispel
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T
Anderson
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Barchi
J J
JJ
Marquez
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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
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