RNA unwinding from reweighted pulling simulations

TL;DR

This study introduces a novel reweighting simulation approach to quantitatively characterize the molecular steps of RNA duplex unwinding, linking free-energy profiles to biological functions and enzyme mechanisms.

Contribution

It presents a new reweighting scheme for analyzing pulling simulations, enabling detailed free-energy profiling of RNA base opening transitions.

Findings

Validated free-energy profiles match experimental data

Revealed molecular motion pathways of helix opening

Linked RNA dynamics to enzyme unwinding mechanisms

Abstract

The forming and melting of complementary base pairs in RNA duplexes are conformational transitions required to accomplish a plethora of biological functions. Yet the dynamic steps of these transitions have not been quantitatively characterized at the molecular level. In this work, the base opening process was first enforced by atomistic pulling simulations and then analyzed with a novel reweighting scheme which allowed the free-energy profile along any suitable reaction coordinate, e.g. solvation, to be reconstructed. The systematic application of such approach to different base-pair combinations provides a molecular motion picture of helix opening which is validated by comparison with an extensive set of experimental observations and links them to the enzyme-dependent unwinding mechanism. The RNA intrinsic dynamics disclosed in this work could rationalize the directionality observed in RNA-processing molecular machineries.