Thumbs Down: Subdomain Rearrangements in the Drug Bound HIV-1 Reverse Transcriptase

Abstract

One of the two main drug targets in human immunodeficiency virus-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 A 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 suggests that the binding of NNRTIs forces RT into a wide open conformation in which the separation is between the thumb and fingers subdomains is much higher that the apo structure. Using multi-copy molecular dynamics simulations (with a cumulative simulation time of approximately 900 ns) we have captured RT bound to the NNRTI efavirenz in a previously uncharacterised closed conformation suggesting that the constraint of thumb motion is not as complete as previously believed. This conformation is similar to that adopted by the apo enzyme but with a modified inter-subdomain hinge. We compare the correlated domain motions of the drug bound and apo enzymes. A more detailed understanding of the mechanism of NNRTI inhibition and the effect of their binding upon domain motion could aid the design of more effective inhibitors and help identify novel allosteric sights.