Cited by 86Protein Structure and DynamicsComputational Drug Discovery MethodsRNA and protein synthesis mechanisms

On the Potential of Machine Learning to Examine the Relationship Between Sequence, Structure, Dynamics and Function of Intrinsically Disordered Proteins

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Lindorff-Larsen, Kresten, Kragelund, Birthe B.·2021·Journal of Molecular Biology

Abstract

Intrinsically disordered proteins (IDPs) constitute a broad set of proteins with few uniting and many diverging properties. IDPs-and intrinsically disordered regions (IDRs) interspersed between folded domains-are generally characterized as having no persistent tertiary structure; instead they interconvert between a large number of different and often expanded structures. IDPs and IDRs are involved in an enormously wide range of biological functions and reveal novel mechanisms of interactions, and while they defy the common structure-function paradigm of folded proteins, their structural preferences and dynamics are important for their function. We here discuss open questions in the field of IDPs and IDRs, focusing on areas where machine learning and other computational methods play a role. We discuss computational methods aimed to predict transiently formed local and long-range structure, including methods for integrative structural biology. We discuss the many different ways in which IDPs and IDRs can bind to other molecules, both via short linear motifs, as well as in the formation of larger dynamic complexes such as biomolecular condensates. We discuss how experiments are providing insight into such complexes and may enable more accurate predictions. Finally, we discuss the role of IDPs in disease and how new methods are needed to interpret the mechanistic effects of genomic variants in IDPs.

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  • Native protein conformations are often described as time-averaged ensembles with Boltzmann-type distributions, especially for IDPs and proteins with IDRs.

    “Native conformations of proteins are often described as time averaged ensembles of conformations with Boltzmann-type distributions, especially IDPs and proteins with IDRs100,101.”

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Research works printed but not linked: 2

  1. Rao, R., Liu, J., Verkuil, R., Meier, J., Canny, J.F., Abbeel, P., Sercu, T., Rives, A., (2021). Msa transformer. bioRxiv,.
  2. Staller, M.V., Ramirez, E., Holehouse, A.S., Pappu, R.V., Cohen, B.A., (2021). Design principles of acidic transcriptional activation domains. bioRxiv,. p. 2020-10. 204.

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Authors
Lindorff-Larsen, K., & Kragelund, B. B.
Affiliations
University of Copenhagen (DK)
Corresponding author
Kragelund, Birthe B.
Venue
Journal of Molecular Biology
Publisher
Elsevier BV
Published
2021-10
Volume
433
Issue
20
Pages
167196
ISSN
0022-2836 (ISSN-L)
OpenAlex
W3170848616
Cited by
85
References
293
Citations by year
2026: 8 · 2025: 15 · 2024: 21 · 2023: 25 · 2022: 12 · 2021: 4
FWCI
1.65
Type
journal article
Language
en
Open access
Locations
  • Journal of Molecular Biology (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
  • arXiv (Cornell University) (submittedVersion)
  • arXiv (Cornell University)
Funders
  • Lundbeck Foundation (R155-2015-2666)
  • Novo Nordisk (NNF18OC0033926)
  • Novo Nordisk Foundation (NNF18OC0033950)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
Keywords
intrinsically disordered proteins, intrinsically disordered regions, machine learning, structure prediction, integrative structural biology, protein dynamics, protein-protein interaction, linear motifs, biomolecular condensates, disease-associated variants, structure-function relationship
MeSH terms
Machine Learning, Amino Acid Sequence, Animals, Humans, Protein Conformation, Protein Folding, Intrinsically Disordered Proteins

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