The effect of the K103N mutation of HIV-1 reverse transcriptase (RT) on the activity of efavirenzanalogues was studied via Monte Carlo/free energy perturbation calculations. The relative foldresistance energies indicate that efavirenz binds to K103N RT in a manner similar to the wild-type enzyme. The improved performance of the quinazolinones against the mutant enzyme isattributed to formation of a more optimal hydrogen-bonding network with bridging watermolecules between the ligands and Glu138.