Thumbs Down for HIV: Domain Level Rearrangements Do Occur in the NNRTI-Bound HIV‑1 Reverse Transcriptase

One of the principal targets in human immunodeficiency
virus type
1 (HIV-1) therapy is the reverse transcriptase (RT) enzyme. Non-nucleoside
RT inhibitors (NNRTIs) are a class of highly specific drugs which
bind to a pocket approximately 10 Å from the polymerase active
site, inhibiting the enzyme allosterically. It is widely believed
that NNRTIs function as “molecular wedges”, disrupting
the region between thumb and palm subdomains of the p66 subunit and
locking the thumb in a wide-open conformation. Crystal structure data
suggest that the binding of NNRTIs forces RT into a wide-open conformation
in which the separation between the thumb and fingers subdomains is
much higher than in the apo structure. Using ensemble molecular dynamics
simulations (aggregate sampling ∼600 ns), we have captured
RT bound to the NNRTI efavirenz in a closed conformation similar to
that of the apo enzyme, suggesting the constraint of thumb motion
is not as complete as previously believed. Rather, our investigation
confirms that a conformational distribution across open and closed
states must exist in the drug-bound enzyme and that allosteric modulation
is effected via the alteration of the kinetic landscape of conformational
transitions upon drug-binding. A more detailed understanding of the
mechanism of NNRTI inhibition and the effect of binding upon domain
motion could aid the design of more effective inhibitors and help
identify novel allosteric sites.