Monte Carlo calculations on HIV-1 reverse transcriptase complexed with the non-nucleoside inhibitor 8-Cl TIBO: contribution of the L100I and Y181C variants to protein stability and biological activity

A computational model of the non-nucleoside inhibitor 8-Cl TIBOcomplexed with HIV-1 reverse transcriptase (RT) was constructedin order to determine the binding free energies. Using MonteCarlo simulations, both free energy perturbation and linearresponse calculations were carried out for the transformationof wild-type RT to two key mutants, Y181C and L100I. The newerlinear response method estimates binding free energies basedon changes in electrostatic and van der Waals energies and solvent-accessiblesurface areas. In addition, the change in stability of the proteinbetween the folded and unfolded states was estimated for eachof these mutations, which are known to emerge upon treatmentwith the inhibitor. Results from the calculations revealed thatthere is a large hydrophobic contribution to protein stabilityin the native, folded state. The calculated absolute free energiesof binding from both the linear response, and also the morerigorous free energy perturbation method, gave excellent agreementwith the experimental differences in activity. The success ofthe relatively rapid linear response method in predicting experimentalactivites holds promise for estimating the activity of the inhibitorsnot only against the wild-type RT, but also against key proteinvariants whose emergence undermines the efficacy of the drugs.