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

J Phys Chem Lett. 2022 Apr 21;13(15):3400-3408. doi: 10.1021/acs.jpclett.2c00359. Epub 2022 Apr 11.

Abstract

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.

MeSH terms

  • Molecular Dynamics Simulation*
  • RNA* / chemistry
  • Scattering, Small Angle
  • Thermodynamics
  • X-Ray Diffraction
  • X-Rays

Substances

  • RNA