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Global Conformational Dynamics of HIV-1 Reverse Transcriptase Bound to Non-Nucleoside Inhibitors
Centre for Computational Science, Department of Chemistry, University College London, London, WC1H 0AJ, UK
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK
* Author to whom correspondence should be addressed.
Received: 1 June 2012; in revised form: 16 July 2012 / Accepted: 17 July 2012 / Published: 26 July 2012
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.
Keywords: HIV-1; reverse transcriptase; non-nucleoside reverse transcriptase inhibitor (NNRTI); nevirapine; efavirenz; molecular dynamics; elastic network model
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Wright, D.W.; Hall, B.A.; Kellam, P.; Coveney, P.V. Global Conformational Dynamics of HIV-1 Reverse Transcriptase Bound to Non-Nucleoside Inhibitors. Biology 2012, 1, 222-244.
Wright DW, Hall BA, Kellam P, Coveney PV. Global Conformational Dynamics of HIV-1 Reverse Transcriptase Bound to Non-Nucleoside Inhibitors. Biology. 2012; 1(2):222-244.
Wright, David W.; Hall, Benjamin A.; Kellam, Paul; Coveney, Peter V. 2012. "Global Conformational Dynamics of HIV-1 Reverse Transcriptase Bound to Non-Nucleoside Inhibitors." Biology 1, no. 2: 222-244.