Disordered flanks prevent peptide aggregation

Sanne Abeln, Daan Frenkel

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Natively unstructured or disordered regions appear to be abundant in eukaryotic proteins. Many such regions have been found alongside small linear binding motifs. We report a Monte Carlo study that aims to elucidate the role of disordered regions adjacent to such binding motifs. The coarse-grained simulations show that small hydrophobic peptides without disordered flanks tend to aggregate under conditions where peptides embedded in unstructured peptide sequences are stable as monomers or as part of small micelle-like clusters. Surprisingly, the binding free energy of the motif is barely decreased by the presence of disordered flanking regions, although it is sensitive to the loss of entropy of the motif itself upon binding. This latter effect allows for reversible binding of the signalling motif to the substrate. The work provides insights into a mechanism that prevents the aggregation of signalling peptides, distinct from the general mechanism of protein folding, and provides a testable hypothesis to explain the abundance of disordered regions in proteins.

Original languageEnglish
Article numbere1000241
JournalPLoS Computational Biology
Volume4
Issue number12
DOIs
Publication statusPublished - Dec 2008

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Peptides
peptide
Aggregation
Agglomeration
peptides
protein
Proteins
Protein folding
Monte Carlo method
protein folding
Protein Folding
Micelles
Entropy
Protein
protein aggregates
micelles
entropy
Free energy
Binding Energy
folding

Cite this

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title = "Disordered flanks prevent peptide aggregation",
abstract = "Natively unstructured or disordered regions appear to be abundant in eukaryotic proteins. Many such regions have been found alongside small linear binding motifs. We report a Monte Carlo study that aims to elucidate the role of disordered regions adjacent to such binding motifs. The coarse-grained simulations show that small hydrophobic peptides without disordered flanks tend to aggregate under conditions where peptides embedded in unstructured peptide sequences are stable as monomers or as part of small micelle-like clusters. Surprisingly, the binding free energy of the motif is barely decreased by the presence of disordered flanking regions, although it is sensitive to the loss of entropy of the motif itself upon binding. This latter effect allows for reversible binding of the signalling motif to the substrate. The work provides insights into a mechanism that prevents the aggregation of signalling peptides, distinct from the general mechanism of protein folding, and provides a testable hypothesis to explain the abundance of disordered regions in proteins.",
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Disordered flanks prevent peptide aggregation. / Abeln, Sanne; Frenkel, Daan.

In: PLoS Computational Biology, Vol. 4, No. 12, e1000241, 12.2008.

Research output: Contribution to JournalArticleAcademicpeer-review

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AU - Abeln, Sanne

AU - Frenkel, Daan

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AB - Natively unstructured or disordered regions appear to be abundant in eukaryotic proteins. Many such regions have been found alongside small linear binding motifs. We report a Monte Carlo study that aims to elucidate the role of disordered regions adjacent to such binding motifs. The coarse-grained simulations show that small hydrophobic peptides without disordered flanks tend to aggregate under conditions where peptides embedded in unstructured peptide sequences are stable as monomers or as part of small micelle-like clusters. Surprisingly, the binding free energy of the motif is barely decreased by the presence of disordered flanking regions, although it is sensitive to the loss of entropy of the motif itself upon binding. This latter effect allows for reversible binding of the signalling motif to the substrate. The work provides insights into a mechanism that prevents the aggregation of signalling peptides, distinct from the general mechanism of protein folding, and provides a testable hypothesis to explain the abundance of disordered regions in proteins.

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