Interactions of conformationally biased north and south 2'-fluoro-2', 3'-dideoxynucleoside 5'-triphosphates with the active site of HIV-1 reverse transcriptase

Biochemistry. 2000 Sep 19;39(37):11205-15. doi: 10.1021/bi001090n.


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.

MeSH terms

  • Anti-HIV Agents / chemistry
  • Binding Sites / drug effects
  • Deoxyadenine Nucleotides / chemistry*
  • Deoxyadenine Nucleotides / metabolism
  • Dideoxyadenosine / analogs & derivatives*
  • Dideoxyadenosine / chemistry*
  • Dideoxyadenosine / metabolism
  • Dideoxynucleotides
  • Dinucleoside Phosphates / chemistry
  • HIV Reverse Transcriptase / antagonists & inhibitors
  • HIV Reverse Transcriptase / chemistry*
  • HIV Reverse Transcriptase / metabolism
  • Humans
  • Models, Chemical
  • Models, Molecular
  • Nuclear Magnetic Resonance, Biomolecular
  • Protein Conformation
  • Reverse Transcriptase Inhibitors / chemistry
  • Thermodynamics
  • Tyrosine / chemistry


  • Anti-HIV Agents
  • Deoxyadenine Nucleotides
  • Dideoxynucleotides
  • Dinucleoside Phosphates
  • Reverse Transcriptase Inhibitors
  • 2',3'-dideoxyadenosine triphosphate
  • lodenosine
  • Tyrosine
  • Dideoxyadenosine
  • HIV Reverse Transcriptase