Sequence-to-conformation relationships of disordered regions tethered to folded domains of proteins
Open accessAbstract
Intrinsically disordered proteins and regions (IDPs/IDRs) are characterized by well-defined sequence-to-conformation relationships (SCRs). These relationships refer to the sequence-specific preferences for average sizes, shapes, residue-specific secondary structure propensities, and amplitudes of multiscale conformational fluctuations. SCRs are discerned from the sequence-specific conformational ensembles of IDPs. A vast majority of IDPs are actually tethered to folded domains (FDs). This raises the question of whether or not SCRs inferred for IDPs are applicable to IDRs tethered to FDs. Here, we use atomistic simulations based on a well-established forcefield paradigm and an enhanced sampling method to obtain comparative assessments of SCRs for 13 archetypal IDRs modeled as autonomous units, as C-terminal tails connected to FDs, and as linkers between pairs of FDs. Our studies uncover a set of general observations regarding context-independent versus context-dependent SCRs of IDRs. SCRs are minimally perturbed upon tethering to FDs if the IDRs are deficient in charged residues and for polyampholytic IDRs where the oppositely charged residues within the sequence of the IDR are separated into distinct blocks. In contrast, the interplay between IDRs and tethered FDs has a significant modulatory effect on SCRs if the IDRs have intermediate fractions of charged residues or if they have sequence-intrinsic conformational preferences for canonical random coils. Our findings suggest that IDRs with context-independent SCRs might be independent evolutionary modules, whereas IDRs with context-dependent SCRs might co-evolve with the FDs to which they are tethered.
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Although there are clear context dependent modulations of intrinsic sequence-ensemble relationships, these modulations range from being negligible to predictable based on the sequence features of IDRs and the types of folded domains to which IDRs are tethered.
“Although there are clear context dependent modulations of intrinsic sequence-ensemble relationships, these modulations range from being negligible to predictable based on the sequence features of IDRs and the types of folded domains to which IDRs are tethered.80,81”
From AlphaFold and Implications for Intrinsically Disordered Proteins (2021) · cites this paper as [80]
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AlphaFold and Implications for Intrinsically Disordered Proteins
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- Authors
- Mittal, A., Holehouse, A. S., Cohan, M. C., & Pappu, R. V.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- Pappu, Rohit V.
- Venue
- Journal of Molecular Biology
- Publisher
- Elsevier BV
- Published
- 2018-08
- Volume
- 430
- Issue
- 16
- Pages
- 2403-2421
- ISSN
- 0022-2836 (ISSN-L)
- OpenAlex
- W2801285438
- Cited by
- 72
- References
- 92
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 10 · 2023: 8 · 2022: 9 · 2021: 12 · 2020: 9 · 2019: 10 · 2018: 3
- FWCI
- 3.01
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Molecular Biology (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Science Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Physical Sciences › Chemistry › Physical and Theoretical Chemistry › Advanced Physical and Chemical Molecular Interactions
- Keywords
- intrinsically disordered regions, charged residues, random coil, protein conformational ensembles, protein evolution, C-terminal tail, protein linkers
- MeSH terms
- Protein Domains, Amino Acid Sequence, Animals, Humans, Models, Molecular, Protein Structure, Secondary, Protein Folding, Intrinsically Disordered Proteins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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