Magnesium ions mitigate metastable states in the regulatory landscape of mRNA elements

Ding, Erdong; Chaudhury, Susmit Narayan; Prajapati, Jigneshkumar Dahyabhai; Onuchic, José N.; Sanbonmatsu, Karissa Y.

doi:10.1261/rna.079767.123

Title: Magnesium ions mitigate metastable states in the regulatory landscape of mRNA elements

Journal Article · 22 May 2024 · RNA

DOI: https://doi.org/10.1261/rna.079767.123 · OSTI ID:2470543

Ding, Erdong ^[1]; Chaudhury, Susmit Narayan ^[2]; Prajapati, Jigneshkumar Dahyabhai ^[2]; Onuchic, José N. ^[1]; Sanbonmatsu, Karissa Y. ^[3]

Rice Univ., Houston, TX (United States)
Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
Los Alamos National Laboratory (LANL), Los Alamos, NM (United States); New Mexico Consortium, Los Alamos, NM (United States)

Residing in the 5' untranslated region of the mRNA, the 2'-deoxyguanosine (2'-dG) riboswitch mRNA element adopts an alternative structure upon binding of the 2'-dG molecule, which terminates transcription. RNA conformations are generally strongly affected by positively charged metal ions (especially Mg²⁺). We have quantitatively explored the combined effect of ligand (2'-dG) and Mg²⁺binding on the energy landscape of the aptamer domain of the 2'-dG riboswitch with both explicit solvent all-atom molecular dynamics simulations (99 μsec aggregate sampling for the study) and selective 2'-hydroxyl acylation analyzed by primer extension (SHAPE) experiments. We show that both ligand and Mg²⁺are required for the stabilization of the aptamer domain; however, the two factors act with different modalities. The addition of Mg²⁺remodels the energy landscape and reduces its frustration by the formation of additional contacts. In contrast, the binding of 2'-dG eliminates the metastable states by nucleating a compact core for the aptamer domain. Mg²⁺ions and ligand binding are required to stabilize the least stable helix, P1 (which needs to unfold to activate the transcription platform), and the riboswitch core formed by the backbone of the P2 and P3 helices. Mg²⁺and ligand also facilitate a more compact structure in the three-way junction region.

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Research Organization:: Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)

Sponsoring Organization:: USDOE; National Institutes of Health (NIH); National Science Foundation (NSF)

Grant/Contract Number:: 89233218CNA000001

OSTI ID:: 2470543

Journal Information:: RNA, Journal Name: RNA Journal Issue: 8 Vol. 30; ISSN 1355-8382

Publisher:: Cold Spring Harbor Laboratory PressCopyright Statement

Country of Publication:: United States

Language:: English

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