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.