Relative Importance of Hydrophobicity, Net Charge, and Secondary Structure Propensities in Protein Aggregation

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Abstract

A full understanding of the mechanism by which proteins and peptides convert from their soluble states into amyloid aggregates requires a detailed elucidation of the sequence and structural determinants that govern the processes of amyloid formation. The experimental results collected in the past few years converge on the idea that hydrophobicity, propensity to form a secondary structure and charge are key determinants of aggregation. The effect of mutations on aggregation and the reasons why particular regions of the sequence are more effective than others in promoting aggregation of unstructured polypeptide chains can be explained on the basis of these physicochemical factors. At present, it is possible to edit algorithms to calculate the relative effects of mutations on aggregation, the absolute aggregation rate of a natively unfolded protein, and to identify regions of the sequence that play key roles in promoting the aggregation process of the whole protein. In addition, because amyloid formation seems to be a shared property of natural proteins, protein sequences appear to have evolved to reduce their propensities to aggregate. One of the strategies by which proteins have achieved this end has been to modulate their aggregation potential by playing with these factors.