Abstract
The determination of factors that influence protein conformational changes is very important for the identification of potentially amyloidogenic and disordered regions in polypeptide chains. In our work we introduce a new parameter, mean packing density, to detect both amyloidogenic and disordered regions in a protein sequence. It has been shown that regions with strong expected packing density are responsible for amyloid formation. Our predictions are consistent with known disease-related amyloidogenic regions for eight of 12 amyloid-forming proteins and peptides in which the positions of amyloidogenic regions have been revealed experimentally. Our findings support the concept that the mechanism of amyloid fibril formation is similar for different peptides and proteins. Moreover, we have demonstrated that regions with weak expected packing density are responsible for the appearance of disordered regions. Our method has been tested on datasets of globular proteins and long disordered protein segments, and it shows improved performance over other widely used methods. Thus, we demonstrate that the expected packing density is a useful value with which one can predict both intrinsically disordered and amyloidogenic regions of a protein based on sequence alone. Our results are important for understanding the structural characteristics of protein folding and misfolding.
Highlights
Amyloid fibril formation is associated with an increase of b structure content, which leads to fibrillar aggregation [1]
In addition to proteins observed in amyloid diseases, recent studies have shown that diverse proteins not related to any amyloid disease can aggregate into fibrils under destabilizing conditions [4À6]
We considered the following values the thresholds for predicting amyloidogenic regions: packing density greater than 21.5 and 21.4 for the two scales obtained from database 25% and database 80%, correspondingly; hydrophobicity less than À0.75, and b sheet propensity less than À0.46
Summary
Amyloid fibril formation is associated with an increase of b structure content, which leads to fibrillar aggregation [1]. It should be noted that an increased level of the beta structure is a characteristic property of several different types of protein aggregates (amyloid fibrils, amorphous aggregates) [2,3]. Normal proteins can become toxic when they undergo fibrillation [7]. There is no consensus about toxicity of the different states: small oligomers, large oligomers, protofilaments, protofibrils, filaments, mature fibrils, or amorphous aggregates. Significant advancements in recent research have led to the discovery that the toxic species in the amyloid diseases may not be the fibrils themselves, but rather the pre-fibrillar aggregates [7]. Recognition of the factors that influence protein conformational changes and misfolding is one of the general fundamental problems, the solution to which will help us find effective treatments for amyloid illnesses
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