A Structural and Dynamics Survey of HIV-1 Reverse Transcriptase

Abstract

HIV-1 reverse transcriptase is a critical drug target for HIV treatment, and understanding the exact mechanisms of its function and inhibition would significantly accelerate the development of new anti-HIV drugs. RT is a heterodimeric, multifunctional, multidomain protein with a 66 kDa subunit containing all of the catalytic active sites, and a 51 kDa subunit which is thought to provide structural stability to the larger subunit. Structural information on reverse transcriptase alone has proven to be insufficient to explain the mechanism of inhibition and drug resistance of non-nucleoside reverse transcriptase inhibitors. Elastic network modeling provides a technique to rapidly probe and compare protein dynamics. Combining elastic network modeling with hierarchical clusters of both structural and dynamic data reveals a wealth of novel information. Here we present an extensive survey of the dynamics of reverse transcriptase bound to a variety of ligands with a number of mutations, revealing a novel mechanism for drug resistance to non-nucleoside reverse transcriptase inhibitors, where hydrophobic core mutations subtly shift the position of the thumb subdomain, restoring active-state motion to multiple functionally significant regions of HIV-1 RT. This model arises out of a combination of structural and dynamic information, rather than exclusively from one or the other.