Cargando…
ATP dependent NS3 helicase interaction with RNA: insights from molecular simulations
Non-structural protein 3 (NS3) helicase from hepatitis C virus is an enzyme that unwinds and translocates along nucleic acids with an ATP-dependent mechanism and has a key role in the replication of the viral RNA. An inchworm-like mechanism for translocation has been proposed based on crystal struct...
Autores principales: | , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2015
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4605317/ https://www.ncbi.nlm.nih.gov/pubmed/26358809 http://dx.doi.org/10.1093/nar/gkv872 |
_version_ | 1782395192282710016 |
---|---|
author | Pérez-Villa, Andrea Darvas, Maria Bussi, Giovanni |
author_facet | Pérez-Villa, Andrea Darvas, Maria Bussi, Giovanni |
author_sort | Pérez-Villa, Andrea |
collection | PubMed |
description | Non-structural protein 3 (NS3) helicase from hepatitis C virus is an enzyme that unwinds and translocates along nucleic acids with an ATP-dependent mechanism and has a key role in the replication of the viral RNA. An inchworm-like mechanism for translocation has been proposed based on crystal structures and single molecule experiments. We here perform atomistic molecular dynamics in explicit solvent on the microsecond time scale of the available experimental structures. We also construct and simulate putative intermediates for the translocation process, and we perform non-equilibrium targeted simulations to estimate their relative stability. For each of the simulated structures we carefully characterize the available conformational space, the ligand binding pocket, and the RNA binding cleft. The analysis of the hydrogen bond network and of the non-equilibrium trajectories indicates an ATP-dependent stabilization of one of the protein conformers. Additionally, enthalpy calculations suggest that entropic effects might be crucial for the stabilization of the experimentally observed structures. |
format | Online Article Text |
id | pubmed-4605317 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-46053172015-10-19 ATP dependent NS3 helicase interaction with RNA: insights from molecular simulations Pérez-Villa, Andrea Darvas, Maria Bussi, Giovanni Nucleic Acids Res Computational Biology Non-structural protein 3 (NS3) helicase from hepatitis C virus is an enzyme that unwinds and translocates along nucleic acids with an ATP-dependent mechanism and has a key role in the replication of the viral RNA. An inchworm-like mechanism for translocation has been proposed based on crystal structures and single molecule experiments. We here perform atomistic molecular dynamics in explicit solvent on the microsecond time scale of the available experimental structures. We also construct and simulate putative intermediates for the translocation process, and we perform non-equilibrium targeted simulations to estimate their relative stability. For each of the simulated structures we carefully characterize the available conformational space, the ligand binding pocket, and the RNA binding cleft. The analysis of the hydrogen bond network and of the non-equilibrium trajectories indicates an ATP-dependent stabilization of one of the protein conformers. Additionally, enthalpy calculations suggest that entropic effects might be crucial for the stabilization of the experimentally observed structures. Oxford University Press 2015-10-15 2015-10-10 /pmc/articles/PMC4605317/ /pubmed/26358809 http://dx.doi.org/10.1093/nar/gkv872 Text en © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Computational Biology Pérez-Villa, Andrea Darvas, Maria Bussi, Giovanni ATP dependent NS3 helicase interaction with RNA: insights from molecular simulations |
title | ATP dependent NS3 helicase interaction with RNA: insights from molecular simulations |
title_full | ATP dependent NS3 helicase interaction with RNA: insights from molecular simulations |
title_fullStr | ATP dependent NS3 helicase interaction with RNA: insights from molecular simulations |
title_full_unstemmed | ATP dependent NS3 helicase interaction with RNA: insights from molecular simulations |
title_short | ATP dependent NS3 helicase interaction with RNA: insights from molecular simulations |
title_sort | atp dependent ns3 helicase interaction with rna: insights from molecular simulations |
topic | Computational Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4605317/ https://www.ncbi.nlm.nih.gov/pubmed/26358809 http://dx.doi.org/10.1093/nar/gkv872 |
work_keys_str_mv | AT perezvillaandrea atpdependentns3helicaseinteractionwithrnainsightsfrommolecularsimulations AT darvasmaria atpdependentns3helicaseinteractionwithrnainsightsfrommolecularsimulations AT bussigiovanni atpdependentns3helicaseinteractionwithrnainsightsfrommolecularsimulations |