• ab initio molecular dynamics;
  • Car-Parrinello;
  • HIV reverse transcriptase;
  • low-barrier hydrogen-bond;
  • mutations;
  • resistance


Quantum-chemical methods are used to shed light on the functional role of residues involved in the resistance of HIV-1 reverse transcriptase against nucleoside-analog drugs. Ab initio molecular dynamics simulations are carried out for models representing the adduct between the triphosphate substrate and the nucleoside binding site. The triphosphate is considered either deprotonated or protonated at the γ-position. Although the protonated form already experiences large rearrangements in the ps time scale, the fully deprotonated state exhibits a previously unrecognized low-barrier hydrogen bond between Lys65 and γ-phosphate. Absence of this interaction in Lys65[RIGHTWARDS ARROW]Arg HIV-1 RT might play a prominent role in the resistance of this mutant 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 structure, form a complex H-bond network. Among these waters, one may be crucial for substrate recognition as it bridges Gln151 and Arg72 with the β-phosphate. Absence of this stabilizing interaction in Gln151[RIGHTWARDS ARROW]Met HIV-1 RT mutant may be a key factor for the known drug resistance of this mutant toward dideoxy-type drugs and AZT (Shirasaka T et al., 1995, Proc Natl Acad Sci USA 92:2398–2402; Iversen AK et al., 1996, J Virol 70:1086–1090).