Energetic effects for observed and unobserved HIV-1 reverse transcriptase mutations of residues L100, V106, and Y181 in the presence of nevirapine and efavirenz

The effect of mutations on amino acid residues L100, V106, and Y181 for unbound HIV-1 reverse transcriptase (RT) and RT bound to nevirapine and efavirenz was investigated using Monte Carlo/free energy perturbation calculations. Using both native and bound crystal structures of RT, mutation of the amino acid residues to both those observed and unobserved in patients was carried out. The results of the calculations revealed that the variant that survives in patients dosed with either nevirapine or efavirenz had a more positive ΔΔG value than other variants that were not observed in patients. These data suggest that the mutation observed in patients is the most effective (the one that binds the drug most weakly) of all possible codon change mutations.