Combining simulations and solution experiments as a paradigm for RNA force field refinement

TL;DR

This paper introduces a new paradigm for RNA force field refinement by combining molecular dynamics simulations with experimental data using a maximum entropy approach, improving accuracy and transferability.

Contribution

It proposes a novel scheme that explicitly accounts for noise in measurements and models, enabling chemically consistent corrections to RNA force fields based on diverse experimental data.

Findings

Correctly reproduces experimental data on nucleosides and dinucleosides.

Demonstrates transferability of corrections to tetranucleotides with improved agreement.

Provides a self-consistent framework for integrating multiple experimental datasets.

Abstract

Recent computational efforts have shown that the current potential energy models used in molecular dynamics are not accurate enough to describe the conformational ensemble of RNA oligomers and suggest that molecular dynamics should be complemented with experimental data. We here propose a scheme based on the maximum entropy principle to combine simulations with bulk experiments. In the proposed scheme the noise arising from both the measurements and the forward models used to back calculate the experimental observables is explicitly taken into account. The method is tested on RNA nucleosides and is then used to construct chemically consistent corrections to the Amber RNA force field that allow a large set of experimental data on nucleosides and dinucleosides to be correctly reproduced. The transferability of these corrections is assessed against independent data on tetranucleotides and displays a previously unreported agreement with experiments. This procedure can be applied to enforce multiple experimental data on multiple systems in a self-consistent framework thus suggesting a new paradigm for force field refinement.