Refining the RNA Force Field with Small-Angle X-ray Scattering of Helix-Junction-Helix RNA

: The growing recognition of the functional and therapeutic roles played by RNA and the difficulties in gaining atomic-level insights by experiments are paving the way for all-atom simulations of RNA. One of the main impediments to the use of all-atom simulations is the imbalance between the energy terms of the RNA force fields. Through exhaustive sampling of an RNA helix-junction-helix (HJH) model using enhanced sampling, we critically assessed the select Amber force fields against small-angle X-ray scattering (SAXS) experiments. The tested AMBER99SB, DES-AMBER, and CUFIX force fields show deviations from measured profiles. First, we identified parameters leading to inconsistencies. Then, as a way to balance the forces governing RNA folding, we adopted strategies to refine hydrogen bonding, backbone, and base-stacking parameters. We validated the modified force field (HB-CUFIX) against SAXS data of the HJH model in different ionic strengths. Moreover, we tested a set of independent RNA systems to cross-validate the force field. Overall, HB-CUFIX demonstrates improved performance in studying thermodynamics and structural properties of realistic RNA motifs.

Automated summary

This article highlights the growing recognition of RNA's functional and therapeutic roles and the difficulties in gaining atomic-level insights through experiments. It explores the use of all-atom simulations to overcome these challenges and assesses the performance of different force fields against small-angle X-ray scattering experiments. The study identifies inconsistencies in existing force fields and proposes a modified force field, HB-CUFIX, which exhibits improved performance in studying the thermodynamics and structural properties of realistic RNA motifs.