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.

ATP dependent NS3 helicase interaction with RNA: insights from molecular simulations / Perez Villa, Andrea; Darvas, Maria; Bussi, Giovanni. - In: NUCLEIC ACIDS RESEARCH. - ISSN 0305-1048. - 43:18(2015), pp. 8725-8734. [10.1093/nar/gkv872]

ATP dependent NS3 helicase interaction with RNA: insights from molecular simulations

Perez Villa, Andrea;Darvas, Maria;Bussi, Giovanni
2015-01-01

Abstract

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.
2015
43
18
8725
8734
https://arxiv.org/abs/1508.05199
http://europepmc.org/articles/PMC4605317
http://europepmc.org/articles/PMC4824087
Perez Villa, Andrea; Darvas, Maria; Bussi, Giovanni
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11767/14395
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