Prediction of Amyloidogenic and Disordered Regions in Protein Chains

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.

Synopsis

Protein folding is one of the most challenging issues in biophysical science. During the past few years it has been shown that some diseases are connected with protein misfolding and the formation of insoluble aggregates called amyloid plaques. These processes may be associated with several diseases such as Alzheimer disease, Parkinson disease, Creutzfeldt-Jacob disease, and even certain forms of cancer. It has been shown that proteins with intrinsically disordered regions are involved in protein–protein or protein–nucleic acid interactions. The main objective of this paper is to report insights into the molecular mechanisms of amyloid aggregation. This has been done using the parameter of the observed number of contacts for each amino acid residue in globular state, further called expected packing density. By analysis of sequences alone, the authors have demonstrated that regions that possess strong expected packing density can be responsible for amyloidogenic properties of a protein, while regions with weak expected packing density correspond to disordered regions. A new concept is proposed that could aid in understanding protein folding, misfolding, and amyloidosis. The results help to explain that the nature of the amyloidogenic propensity of proteins is connected to their amino acid sequences that are able to form a large number of contacts.