Using Molecular Simulations to Explore Conformational Transitions in the Hepatitis C Virus Polymerase
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2017-01-01
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Chemistry & Biochemistry
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Biochemistry
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Distribution Rights granted to UMBC by the author.
Distribution Rights granted to UMBC by the author.
Abstract
Hepatitis C virus (HCV) is a global health concern for which there is no vaccine available. The HCV polymerase is responsible for the critical function of replicating the RNA genome of the virus. Transitions between its conformations are necessary for the appropriate functioning of the enzyme in the replication of the enzyme'sRNA. We have shown that one can generate the free energy landscape (FEL) of the free enzyme by combining the results from Molecular Dynamic (MD) simulations initiated from a collection of X-ray structures of NS5B without inhibitor bound. MD is a suitable tool for this purpose since it provides structural and dynamic information regarding the conformational space sampled by the enzyme. From these results, we have elucidated key interactions that stabilize each conformation and that modulate the transitions between them. This new knowledge is essential to gain insight on the role of these conformations in replication and may be also valuable in suggesting novel targets for inhibition of the enzyme. Furthermore, by comparing these observations with the results of MD simulations of inhibitor bound systems, we gained a deeper understanding on the allosteric mechanisms of currently reported inhibitors. As a result, the knowledge garnered from this computational study may be instrumental for improving HCV therapies and those of other related viruses.