Disordered Flanks Prevent Peptide Aggregation

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.Author Summary: In their natural cellular environment proteins are dissolved in a concentrated aqueous solution of biomolecules. Even under such crowded conditions, proteins must not clump together or aggregate; otherwise their biological functions may be compromised, and the cell could die. Diseases such as Parkinson and Alzheimer are thought to be caused by aggregation of specific proteins. Evolutionary pressure generally ensures that proteins do not aggregate in their natural biochemical environment. A well-known mechanism to prevent aggregation is the folding of proteins, where the hydrophobic (attractive) part of the protein is buried inside the protein. Here we report a different mechanism that can prevent the aggregation of proteins. Recently, it was discovered that many proteins contain regions that are disordered (not folded) in their natural environment. We show with coarse-grained simulations that aggregation of small hydrophobic binding motifs can be prevented by embedding the motifs in disordered regions: the disordered regions of different proteins obstruct or sterically hinder the formation of aggregates. Moreover, our simulations show that the disordered regions have no adverse effect on the biological function of the binding motifs, because they do not obstruct the binding and folding of the binding motif on its specific substrate.