Allosteric Inhibitors Have Distinct Effects, but Also Common Modes of Action, in the HCV Polymerase

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dc.contributor.authorDavis, Brittny C.
dc.contributor.authorBrown, Jodian A.
dc.contributor.authorThorpe, Ian F.
dc.date.accessioned2018-10-01T14:00:22Z
dc.date.available2018-10-01T14:00:22Z
dc.date.issued2016-11-15
dc.description.abstractThe RNA-dependent RNA polymerase from the Hepatitis C Virus (gene product NS5B) is a validated drug target because of its critical role in genome replication. There are at least four distinct allosteric sites on the polymerase to which several small molecule inhibitors bind. In addition, numerous crystal structures have been solved with different allosteric inhibitors bound to the polymerase. However, the molecular mechanisms by which these small molecules inhibit the enzyme have not been fully elucidated. There is evidence that allosteric inhibitors alter the intrinsic motions and distribution of conformations sampled by the enzyme. In this study we use molecular dynamics simulations to understand the structural and dynamic changes that result when inhibitors are bound at three different allosteric binding sites on the enzyme. We observe that ligand binding at each site alters the structure and dynamics of NS5B in a distinct manner. Nonetheless, our studies also highlight commonalities in the mechanisms of action of the different inhibitors. Each inhibitor alters the conformational states sampled by the enzyme, either by rigidifying the enzyme and preventing transitions between functional conformational states or by destabilizing the enzyme and preventing functionally relevant conformations from being adequately sampled. By illuminating the molecular mechanisms of allosteric inhibition, these studies delineate the intrinsic functional properties of the enzyme and pave the way for designing novel and more effective polymerase inhibitors. This information may also be important to understand how allosteric regulation occurs in related viral polymerases and other enzymes.en_US
dc.description.sponsorshipThe hardware used in the computational studies is part of the University of Maryland, Baltimore County High Performance Computing Facility. The facility is supported by the U.S. National Science Foundation through the Major Research Instrumentation program (grant Nos. CNS-0821258 and CNS-1228778) and the Scientific Computing Research Environments for the Mathematical Sciences program (grant no. DMS-0821311), with additional substantial support from the University of Maryland, Baltimore County. This work also used the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by National Science Foundation grant number ACI-1053575. In addition, B.D. and J.B. were funded by National Institutes of Health NIH-F31 grants (Nos. GM106959-01 and GM106958-01, respectively).en_US
dc.description.urihttps://www.sciencedirect.com/science/article/pii/S0006349516309420?via%3Dihub#!en_US
dc.format.extent11 pagesen_US
dc.genrejournal articleen_US
dc.identifierdoi:10.13016/M2TD9NC3W
dc.identifier.citationBrittny C. Davis, Jodian A. Brown, Ian F. Thorpe Allosteric Inhibitors Have Distinct Effects, but Also Common Modes of Action, in the HCV Polymerase Biophysical Journal, Volume 108, Issue 7, 7 April 2015, Pages 1785-1795, https://doi.org/10.1016/j.bpj.2016.10.015en_US
dc.identifier.urihttps://doi.org/10.1016/j.bpj.2016.10.015
dc.identifier.urihttp://hdl.handle.net/11603/11420
dc.language.isoen_USen_US
dc.relation.isAvailableAtThe University of Maryland, Baltimore County (UMBC)
dc.relation.ispartofUMBC Chemistry & Biochemistry Department Collection
dc.relation.ispartofUMBC Faculty Collection
dc.rightsThis item is likely protected under Title 17 of the U.S. Copyright Law. Unless on a Creative Commons license, for uses protected by Copyright Law, contact the copyright holder or the author.
dc.subjectUMBC High Performance Computing Facility (HPCF)
dc.subjectRNA polymerase from the Hepatitis C Virus
dc.subjectgene product NS5B
dc.subjectallosteric inhibitors
dc.subjectmolecular dynamics simulations
dc.titleAllosteric Inhibitors Have Distinct Effects, but Also Common Modes of Action, in the HCV Polymeraseen_US
dc.typeTexten_US

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