3D RNA and Functional Interactions from Evolutionary Couplings
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Abstract
Non-coding RNAs are ubiquitous, but the discovery of new RNA gene sequences far outpaces the research on the structure and functional interactions of these RNA gene sequences. We mine the evolutionary sequence record to derive precise information about the function and structure of RNAs and RNA-protein complexes. As in protein structure prediction, we use maximum entropy global probability models of sequence co-variation to infer evolutionarily constrained nucleotide-nucleotide interactions within RNA molecules and nucleotide-amino acid interactions in RNA-protein complexes. The predicted contacts allow all-atom blinded 3D structure prediction at good accuracy for several known RNA structures and RNA-protein complexes. For unknown structures, we predict contacts in 160 non-coding RNA families. Beyond 3D structure prediction, evolutionary couplings help identify important functional interactions-e.g., at switch points in riboswitches and at a complex nucleation site in HIV. Aided by increasing sequence accumulation, evolutionary coupling analysis can accelerate the discovery of functional interactions and 3D structures involving RNA.
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The deeper layers of current transformer-based PLMs focus relatively more on learning protein contacts, whereas secondary structure information is spread more evenly across both shallow and deep layers.
“An important observation is that the deeper layers of current transformer-based PLMs focus relatively more on learning protein contacts, whereas the secondary structure information is spread more evenly across both shallow and deep layers (15).”
From High-resolution <i>de novo</i> structure prediction from primary sequence (2022) · cites this paper as [15]
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3D protein structure from genetic epistasis experimentsPreprint
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Self-citationZerihun, M. B., & Schug, A. H. (2017) · Biochemical Society Transactions · doi:10.1042/bst20170063 · Cited by 8 · see citing works
Structure and evolution-guided design of minimal RNA-guided nucleases
Skopintsev, P., Esain-Garcia, I., DeTurk, E. C., Yoon, P. H., Zhou, Z., Weiss, T. J., Kamalu, M., Chamraj, A., Loi, K. J., Langeberg, C. J., et al. (2026) · Science · doi:10.1126/science.aed6123 · Cited by 8 · see citing works
Huang, Y. J., Brock, K. P., Sander, C., Marks, D. S., & Montelione, G. T. (2018) · Advances in experimental medicine and biology · doi:10.1007/978-981-13-2200-6_10 · Cited by 7 · see citing works
Self-citation
- Authors
- Weinreb, C., Riesselman, A. J., Ingraham, J. B., Gross, T., Sander, C., & Marks, D. S.
- Affiliations
- Harvard University (US)
- Corresponding author
- Marks, Debora S.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2016-05
- Volume
- 165
- Issue
- 4
- Pages
- 963-975
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5024353
- OpenAlex
- W2342307854
- Cited by
- 159
- References
- 116
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 14 · 2023: 4 · 2022: 21 · 2021: 13 · 2020: 24 · 2019: 18 · 2018: 27 · 2017: 20 · 2016: 4
- FWCI
- 11.96
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- arXiv (Cornell University) (submittedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- Funders
- DOE (DE-FG02-97ER25308)
- NSF Graduate Research Fellowship
- NIH (R01 GM106303)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
- Keywords
- evolutionary coupling, RNA structure prediction, protein-RNA complex, non-coding RNA, maximum entropy model, riboswitches, HIV, functional interactions, RNA tertiary structure
- MeSH terms
- Models, Molecular, Nucleic Acid Conformation, Ribosomes, RNA-Binding Proteins, Evolution, Molecular, Entropy, RNA, Untranslated, RNA Folding
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