Ab initio molecular dynamics studies on HIV-1 reverse transcriptase triphosphate binding site: Implications for nucleoside-analog drug resistance

Quantum-chemical methods are used to shed light on the functional role of r esidues involved in the resistance of HIV-1 reverse transcriptase against n ucleoside-analog drugs. Ab initio molecular dynamics simulations are carrie d out for models representing the adduct between the triphosphate substrate and the nucleoside binding site. The triphosphate is considered either dep rotonated or protonated at the gamma -position. Although the protonated for m already experiences large rearrangements in the ps time scale, the fully deprotonated state exhibits a previously unrecognized low-barrier hydrogen bond between Lys65 and gamma -phosphate. Absence of this interaction in Lys 65-->Arg HIV-I RT might play a prominent role in the resistance of this mut ant for nucleoside analogs (Gu Z et al., 1994b, Antimicrob Agents Chemother 38:275-281; Zhang D et al., 1994. Antimicrob Agents Chemother 38:282-287). Water molecules present in the active site, not detected in the X-ray stru cture, form a complex H-bond network. Among these waters, one may be crucia l for substrate recognition as it bridges Gln151 and Arg72 with the beta -p hosphate. Absence of this stabilizing interaction in Gln151-->Met HIV-1 RT mutant may be a key factor for the known drug resistance of this mutant tow ard dideoxy-type drugs and AZT (Shirasaka T et al., 1995, Proc Natl Acad Sc i USA 92:2398-2402; Iversen AK et al., 1996, J Virol 70:1086-1090).