Inhibitor binding
alters the directions of domain motions in HIV-1 reverse transcriptase
Understanding the molecular mechanisms of HIV-1 reverse transcriptase (RT)
action and drug inhibition is essential for designing effective
anti-retroviral therapies. While comparisons of the different crystal
forms of RT give insights into the flexibility of different domains, a
direct computational assessment of the effect of inhibitor binding on the
collective dynamics of RT is lacking. A structure-based approach is used
here for exploring the dynamics of RT in unliganded and inhibitor-bound
forms. Non nucleoside RT inhibitors are shown to interfere directly with
the global hinge-bending mechanism that controls the cooperative motions
of the p66 fingers and thumb subdomains. The net effect of nevirapine
binding is to change the direction of domain movements rather than
suppress their mobilities. The second generation NNRTI, efavirenz, on the
other hand, shows the stronger effect of simultaneously reorienting domain
motions and obstructing the p66 thumb fluctuations. A second hinge site
controlling the global rotational reorientations of the RNase H domain is
identified, which could serve as a target for potential inhibitors of
RNase H activity.
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