A simple algorithm locates β‐strands in the amyloid fibril core of α‐synuclein, Aβ, and tau using the amino acid sequence alone

Abstract

Fibrillar inclusions are a characteristic feature of the neuropathology found in the α‐synucleinopathies such as Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Familial forms of α‐synucleinopathies have also been linked with missense mutations or gene multiplications that result in higher protein expression levels. In order to form these fibrils, the protein, α‐synuclein (α‐syn), must undergo a process of self‐assembly in which its native state is converted from a disordered conformer into a β‐sheet‐dominated form. Here, we have developed a novel polypeptide property calculator to locate and quantify relative propensities for β‐strand structure in the sequence of α‐syn. The output of the algorithm, in the form of a simple x‐y plot, was found to correlate very well with the location of the β‐sheet core in α‐syn fibrils. In particular, the plot features three peaks, the largest of which is completely absent for the nonfibrillogenic protein, β‐syn. We also report similar significant correlations for the Alzheimer's disease‐related proteins, Aβ and tau. A substantial region of α‐syn is also of converting from its disordered conformation into a long amphipathic α‐helical protein. We have developed the aforementioned algorithm to locate and quantify the α‐helical hydrophobic moment in the amino acid sequence of α‐syn. As before, the output of the algorithm, in the form of a simple x‐y plot, was found to correlate very well with the location of α‐helical structure in membrane bilayer‐associated α‐syn.