TY - JOUR
T1 - Refining the RNA Force Field with Small-Angle X-ray Scattering of Helix-Junction-Helix RNA
AU - He, Weiwei
AU - Naleem, Nawavi
AU - Kleiman, Diego
AU - Kirmizialtin, Serdal
N1 - Funding Information:
This research was carried out on the High Performance Computing resources at New York University Abu Dhabi and supported by an AD181 faculty research grant. The authors thank Lois Pollack and Yen-Lin Chen for valuable discussions and for kindly providing the SAXS data.
Publisher Copyright:
© 2022 American Chemical Society. All rights reserved.
PY - 2022/4/21
Y1 - 2022/4/21
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.jpclett.2c00359
DO - 10.1021/acs.jpclett.2c00359
M3 - Article
C2 - 35404614
AN - SCOPUS:85128793664
SN - 1948-7185
VL - 13
SP - 3400
EP - 3408
JO - Journal of Physical Chemistry Letters
JF - Journal of Physical Chemistry Letters
IS - 15
ER -