Global Conformational Dynamics of HIV-1 Reverse Transcriptase Bound to Non-Nucleoside Inhibitors

Abstract

HIV-1 Reverse Transcriptase (RT) is a multifunctional enzyme responsible for the transcription of the RNA genome of the HIV virus into DNA suitable for incorporation within the DNA of human host cells. Its crucial role in the viral life cycle has made it one of the major targets for antiretroviral drug therapy. The Non-Nucleoside RT Inhibitor (NNRTI) class of drugs binds allosterically to the enzyme, affecting many aspects of its activity. We use both coarse grained network models and atomistic molecular dynamics to explore the changes in protein dynamics induced by NNRTI binding. We identify changes in the flexibility and conformation of residue Glu396 in the RNaseH primer grip which could provide an explanation for the acceleration in RNaseH cleavage rate observed experimentally in NNRTI bound HIV-1 RT. We further suggest a plausible path for conformational and dynamic changes to be communicated from the vicinity of the NNRTI binding pocket to the RNaseH at the other end of the enzyme.

A Polymorphism at Position 400 in the Connection Subdomain of HIV-1 Reverse Transcriptase Affects Sensitivity to NNRTIs and RNaseH Activity

“…Only a single peak is found in the χ 1 angle distribution for the A400T enzyme, and a bimodal distribution is observed for the wild-type (Fig 5B). As we have previously shown [33], this region is also impacted by the binding of NVP with both RT enzymes showing bimodal distributions with peaks around 90° and 170° (Fig 5C). In wild-type RT, the 170° angle is more frequently observed, whereas the 90° angle is more frequent for A400T.…”

“…In p66 these residues are located in a solvent exposed helix far from the functionally significant regions of the protein (see Fig S1 in File S1). We have previously demonstrated that the region around αL in p51 can be impacted by the binding of NVP [33]. The aim of our simulations is to test whether the change at position 400 alters the dynamics of residues in the RNaseH primer grip and whether any such changes are correlated with alterations in the template/primer trajectory or conformation.…”

“…Moreover, we explored the molecular mechanisms involved in resistance and show that it reduces RNaseH activity. Computer simulations provide a powerful tool that allows us to elucidate the atomistic origins of such changes in protein function [33]. Here we apply molecular dynamics simulations techniques to model the effects of the alanine to threonine change at position 400 on RT structure at the atomistic level.…”

Structure of the HIV-1 reverse transcriptase Q151M mutant: insights into the inhibitor resistance of HIV-1 reverse transcriptase and the structure of the nucleotide-binding pocket ofHepatitis B viruspolymerase

“…2). It is known that the thumb subdomain can exhibit 'open' and 'closed' conformations in the DNA-bound or NRTI-bound HIV-1 RT structures and unliganded structures, respectively (Hsiou et al, 1996;Wright et al, 2012). The displacement of each residue between p66 of HIV-1 RT Q151M and that of other HIV-1 RTs in the open conformation (PDB entries 1rth, 3htv and 2rf2) showed a large movement of the thumb subdomain ($25 Å ) and a slight movement of the other subdomains ($5 Å ) (Figs.…”

Conformational Plasticity of the NNRTI-Binding Pocket in HIV-1 Reverse Transcriptase: A Fluorine Nuclear Magnetic Resonance Study

“…19,20 In addition, several computational studies have been conducted to characterize RT dynamics and the effects of NNRTI binding. 21–28 Yet, a general consensus on the mechanistic basis for NNRTI inhibition of RT has not been reached. 2,12,29,30 …”