4.7 Review

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

Journal

JOURNAL OF MOLECULAR BIOLOGY
Volume 433, Issue 20, Pages -

Publisher

ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2021.167196

Keywords

machine learning; intrinsically disordered protein; molecular complex; condensate; SLiM

Funding

  1. Novo Nordisk Challenge Programme REPIN [NNF18OC0033926]
  2. Lundbeck Foundation BRAINSTRUC initiative in structural biology [R155-2015-2666]
  3. Novo Nordisk Challenge Programme PRISM [NNF18OC0033950]

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Intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) play important roles in a wide range of biological functions and reveal novel mechanisms of interactions. Computational methods, including machine learning, are crucial for predicting the structures and functions of IDPs and IDRs. Experiments provide insights into complexes and may enable more accurate predictions.
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. (C) 2021 The Author(s). Published by Elsevier Ltd.

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