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Peer-reviewedCC BY-NC-ND 4.0Journal of Chemical Information and Modeling

Nonadditive Conformational Effects of tRNA Core Modifications

  • Teddy E. Amissah1
  • Lev Levintov1
  • Harish Vashisth1,2,3,4
4 affiliations
  1. 1Department of Chemical Engineering and Bioengineering, University of New Hampshire, Durham, New Hampshire 03824, United States
  2. 2Department of Chemistry, University of New Hampshire, Durham, New Hampshire 03824, United States
  3. 3Integrated Applied Mathematics Program, University of New Hampshire, Durham, New Hampshire 03824, United States
  4. 4Molecular and Cellular Biotechnology Program, University of New Hampshire, Durham, New Hampshire 03824, United States
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Abstract

Post-transcriptional modifications are known to regulate the structure and function of tRNA molecules. Compared to modifications in the anticodon region, the mechanistic effects of modifications in the core region of tRNA remain poorly understood. Using all-atom molecular dynamics (MD) simulations on yeast tRNAPhe, we investigated the conformational effects of incorporating chemical modifications in the core region (termed hereafter “core modifications”) of tRNA. Specifically, we focused on three core modifications, namely, 7-methylguanosine (m7G), 5-methylcytosine (m5C), and 1-methyladenosine (m1A). We discovered that individual modifications increased the structural stability of tRNA, but their combinations produced multimodal free energy landscapes with multiple distinct basins. We identified m1A58 as a bifunctional regulator that locally disrupts structure while globally coordinating anticorrelated arm movement. The combination of m1A58 and m5C49 exhibited the lowest structural deviation from the crystal structure, while the triply modified variant incorporating all three modifications produced the most integrated residue community network, reflecting nonadditive allosteric coupling that cannot be predicted from any pairwise combination. Critically, core modifications established extensive allosteric pathways that prevent the consistent inward displacement of the anticodon stem loop otherwise observed in all simulations of chemically unmodified tRNA. Our results demonstrate that core modifications function as regulators of conformational ensembles rather than simple stabilizers.

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Cite

BibTeXRIS
BibTeX
@article{amissah2026nonadditive,
  title = {{Nonadditive Conformational Effects of tRNA Core Modifications}},
  author = {Teddy E. Amissah and Lev Levintov and Harish Vashisth},
  journal = {Journal of Chemical Information and Modeling},
  year = {2026},
  month = oct,
  doi = {10.1021/acs.jcim.6c02045},
  url = {https://doi.org/10.1021/acs.jcim.6c02045},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - Nonadditive Conformational Effects of tRNA Core Modifications
AU  - Teddy E. Amissah
AU  - Lev Levintov
AU  - Harish Vashisth
PY  - 2026
DA  - 2026/10/08
JO  - Journal of Chemical Information and Modeling
DO  - 10.1021/acs.jcim.6c02045
UR  - https://doi.org/10.1021/acs.jcim.6c02045
AB  - Post-transcriptional modifications are known to regulate the structure and function of tRNA molecules. Compared to modifications in the anticodon region, the mechanistic effects of modifications in the core region of tRNA remain poorly understood. Using all-atom molecular dynamics (MD) simulations on yeast tRNAPhe, we investigated the conformational effects of incorporating chemical modifications in the core region (termed hereafter “core modifications”) of tRNA. Specifically, we focused on three core modifications, namely, 7-methylguanosine (m7G), 5-methylcytosine (m5C), and 1-methyladenosine (m1A). We discovered that individual modifications increased the structural stability of tRNA, but their combinations produced multimodal free energy landscapes with multiple distinct basins. We identified m1A58 as a bifunctional regulator that locally disrupts structure while globally coordinating anticorrelated arm movement. The combination of m1A58 and m5C49 exhibited the lowest structural deviation from the crystal structure, while the triply modified variant incorporating all three modifications produced the most integrated residue community network, reflecting nonadditive allosteric coupling that cannot be predicted from any pairwise combination. Critically, core modifications established extensive allosteric pathways that prevent the consistent inward displacement of the anticodon stem loop otherwise observed in all simulations of chemically unmodified tRNA. Our results demonstrate that core modifications function as regulators of conformational ensembles rather than simple stabilizers.
SN  - 1549-9596
SN  - 1549-960X
ER  -