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, βFddATP, and αFddATP, explain the experimentally observed order of potency of these 5'-triphosphates as inhibitors of RT: ddATP > βFddATP > αFddATP. On the basis of RT's known preference to bind the incoming dNTP (or ddNTP) with a north conformation at the polymerase site, αFddATP, 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 αFddATP in its preferred north conformation. The south-biased βFddATP, 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 βFddATP. These results highlight the opposite conformational preferences of HIV-1 RT for αFddATP and βFddATP and help establish conformational guidelines for optimal binding at the polymerase site of this enzyme.
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