Automatic structure-based NMR methyl resonance assignment in large proteins
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Abstract
Isotopically labeled methyl groups provide NMR probes in large, otherwise deuterated proteins. However, the resonance assignment constitutes a bottleneck for broader applicability of methyl-based NMR. Here, we present the automated MethylFLYA method for the assignment of methyl groups that is based on methyl-methyl nuclear Overhauser effect spectroscopy (NOESY) peak lists. MethylFLYA is applied to five proteins (28–358 kDa) comprising a total of 708 isotope-labeled methyl groups, of which 612 contribute NOESY cross peaks. MethylFLYA confidently assigns 488 methyl groups, i.e. 80% of those with NOESY data. Of these, 459 agree with the reference, 6 were different, and 23 were without reference assignment. MethylFLYA assigns significantly more methyl groups than alternative algorithms, has an average error rate of 1%, modest runtimes of 0.4–1.2 h, and can handle arbitrary isotope labeling patterns and data from other types of NMR spectra.
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Methyl side-chain NMR assignments can be obtained using only methyl-methyl NOEs from 3D NMR experiments and atomic coordinates of a structure or AF2 model as input with software such as MAUS, MAGIC, and methylFLYA.
“Here, NMR assignments for methyl side-chain groups can be obtained using only methyl-methyl NOEs obtained from 3D NMR experiments and the atomic coordinates of a structure (or AF2 predicted structure) as input with software such as MAUS, MAGIC, and methylFLYA91,93,94.”
From The power and pitfalls of AlphaFold2 for structure prediction beyond rigid globular proteins (2024) · cites this paper as [93]
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References 59 · Cited by 46
- Authors
- Pritišanac, I., Würz, J. M., Alderson, T. R., & Güntert, P.
- Affiliations
- Goethe University Frankfurt (DE)
- National Institutes of Health (US)
- Corresponding author
- Güntert, Peter
- Venue
- Nature Communications
- Published
- 2019-10-29
- Volume
- 10
- Issue
- 1
- Pages
- 4922-4922
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6820720
- OpenAlex
- W2982428589
- Cited by
- 46
- References
- 59
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 3 · 2023: 7 · 2022: 12 · 2021: 6 · 2020: 9 · 2019: 1
- FWCI
- 2.79
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Repository for Publications and Research Data (ETH Zurich) (submittedVersion, cc-by)
- ETH Zürich Research Collection (cc-by)
- Funders
- EC | Eurostars (E!9803)
- MEXT | Japan Society for the Promotion of Science (JP17K07312)
- Topics
- Physical Sciences › Chemistry › Spectroscopy › Advanced NMR Techniques and Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- deuterated proteins, large proteins
- MeSH terms
- Algorithms, Automation, Methylation, Models, Molecular, Molecular Weight, Proteins, Software, Nuclear Magnetic Resonance, Biomolecular
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