FREE-ENERGY PERTURBATION STUDIES ON INHIBITOR BINDING TO HIV-1 PROTEINASE

The free energy perturbation method has been employed to determine the binding free energy contributions of different groups of two classes of HIV-1 proteinase inhibitors: (1) a hydroxyethylene isostere inhibitor, Ala-Ala-Phe[CH(OH)-CH2]Gly-Val-Val-OMe (reported by Dreyer et al. 1), and a reduced peptide inhibitor, MVT-101 (reported by Miller et al. 2). For the first inhibitor, the configuration of the central hydroxyl group is changed from S to R in two steps. In the first step, the hydroxyl group in the S configuration was mutated to a hydrogen, and in the second step, the hydroxyl group of the (R)-OH analogue of the inhibitor was mutated to a hydrogen. In this way the binding contributions of the hydroxyl group in the two diastereomers are determined separately in addition to obtaining the effect of changing the hydroxyl group configuration from S to R. The calculated free energy difference between the binding of the two diastereomers is 3.37 +/- 0.64 kcal/mol, which is close the experimental value of 2.6 kcal/mol. The calculations on the substitution of Gly by Nle at the P'1 position of the same inhibitor predict an enhancement in the binding by about 1.7 kcal/mol. Similar calculations on the substitution of Nle with Met in MVT-101 inhibitor predict a decrease in binding by about 0.7 kcal/mol. The details of these results will be discussed and compared with the results of a similar study on pepstatin-rhizopus pepsin complex.