Two-State RNA Recognition of the FUS RRM Characterized by RNA Sugar Puckering Dynamics
Abstract
The RNA recognition motif (RRM) of Fused in Sarcoma (FUS) targets four nucleotides in the hairpin loop of spliceosomal RNA in a sequence-nonspecific manner. To elucidate the mechanism underlying recognition of RNA hairpin loops by the FUS RRM, we performed molecular dynamics simulations of the FUS RRM–RNA hairpin loop complex. Markov state modeling and free energy landscape analyses revealed two distinct conformational states of RNA within the FUS RRM–RNA complex, governed by microscopic ribose puckering equilibria and base-flipping dynamics. Switching between the two states allows the RNA to adopt multiple binding modes, enabling recognition without reliance on any interactions between specific atom pairs. Consequently, RNA sequence variations that weaken specific interactions can be tolerated through alternative interaction networks. Further systematic base-substitution analysis suggests that the FUS RRM potentially recognizes an NHBN-like sequence motif (N = any, H = A/C/U, and B = U/C/G), broadening the previously proposed NYNY paradigm (Y = C/U). The dynamic and multistate nature of RNA recognition observed here provides a mechanistic basis for the ability of the FUS RRM to interact with diverse RNA targets, including exposed hairpin loops in the spliceosome.
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BibTeX
@misc{kijima2026twostate,
title = {{Two-State RNA Recognition of the FUS RRM Characterized by RNA Sugar Puckering Dynamics}},
author = {Soichiro Kijima and Akio Kitao},
howpublished = {ChemRxiv},
year = {2026},
month = sep,
doi = {10.26434/chemrxiv.15008181/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008181/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Two-State RNA Recognition of the FUS RRM Characterized by RNA Sugar Puckering Dynamics
AU - Soichiro Kijima
AU - Akio Kitao
PY - 2026
DA - 2026/09/01
PB - ChemRxiv
DO - 10.26434/chemrxiv.15008181/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008181/v1
AB - The RNA recognition motif (RRM) of Fused in Sarcoma (FUS) targets four nucleotides in the hairpin loop of spliceosomal RNA in a sequence-nonspecific manner. To elucidate the mechanism underlying recognition of RNA hairpin loops by the FUS RRM, we performed molecular dynamics simulations of the FUS RRM–RNA hairpin loop complex. Markov state modeling and free energy landscape analyses revealed two distinct conformational states of RNA within the FUS RRM–RNA complex, governed by microscopic ribose puckering equilibria and base-flipping dynamics. Switching between the two states allows the RNA to adopt multiple binding modes, enabling recognition without reliance on any interactions between specific atom pairs. Consequently, RNA sequence variations that weaken specific interactions can be tolerated through alternative interaction networks. Further systematic base-substitution analysis suggests that the FUS RRM potentially recognizes an NHBN-like sequence motif (N = any, H = A/C/U, and B = U/C/G), broadening the previously proposed NYNY paradigm (Y = C/U). The dynamic and multistate nature of RNA recognition observed here provides a mechanistic basis for the ability of the FUS RRM to interact with diverse RNA targets, including exposed hairpin loops in the spliceosome.
ER -