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

TL;DR

This study uses molecular dynamics simulations to explore how ATP influences the conformational stability of NS3 helicase during RNA translocation, providing detailed insights into its mechanism.

Contribution

It offers the first atomistic simulation analysis of NS3 helicase's conformational dynamics and ATP-dependent stabilization during RNA translocation.

Findings

ATP stabilizes specific protein conformers

Entropic effects are crucial for structure stabilization

Simulations reveal conformational space and ligand interactions

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.