Reweighting of molecular simulations with explicit-solvent SAXS restraints elucidates ion-dependent RNA ensembles

TL;DR

This paper presents a method combining molecular dynamics and SAXS data to accurately model RNA conformational ensembles, explicitly considering solvent effects and ion-dependent dynamics, enhancing understanding of RNA structure in different ionic conditions.

Contribution

The study introduces a novel integrative approach that combines atomistic simulations with SAXS data, explicitly modeling solvent effects and ion-dependent RNA conformations.

Findings

Explicit-solvent effects are crucial for matching SAXS data.

RNA conformations are significantly ion-dependent.

The method reveals a higher fraction of extended structures in certain ionic conditions.

Abstract

Small-angle X-ray scattering (SAXS) experiments are increasingly used to probe RNA structure. A number of \emph{forward models} that relate measured SAXS intensities and structural features, and that are suitable to model either explicit-solvent effects or solute dynamics, have been proposed in the past years. Here we introduce an approach that integrates atomistic molecular dynamics simulations and SAXS experiments to reconstruct RNA structural ensembles while simultaneously accounting for both RNA conformational dynamics and explicit-solvent effects. Our protocol exploits SAXS pure-solute forward models and enhanced sampling methods to sample an heterogenous ensemble of structures, with no information towards the experiments provided on-the-fly. The generated structural ensemble is then reweighted through the maximum entropy principle so as to match reference SAXS experimental data at multiple ionic conditions. Importantly, accurate explicit-solvent forward models are used at this reweighting stage. We apply this framework to the GTPase-associated center, a relevant RNA molecule involved in protein translation, in order to elucidate its ion-dependent conformational ensembles. We show that (a) both solvent and dynamics are crucial to reproduce experimental SAXS data and (b) the resulting dynamical ensembles contain an ion-dependent fraction of extended structures.