Uncovering the Binding and Specificity of -Wrapins for Amyloid- and -Synuclein.
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abstract
Amyloidogenic proteins amyloid- peptide (A) and -synuclein (-syn) self-assemble into fibrillar amyloid deposits, senile plaques and Lewy bodies, pathological features of Alzheimer's and Parkinson's diseases, respectively. Interestingly, a portion of Alzheimer's disease cases also exhibit aggregation of -syn into Lewy bodies, and growing evidence also suggests that A and -syn oligomers are toxic. Therefore, the simultaneous inhibition through sequestration of the two amyloidogenic proteins may constitute a promising therapeutic strategy. Recently discovered -wrapin proteins pave the way toward this direction as they can inhibit the aggregation and toxicity of both A and -syn. Here, we used computational methods, primarily molecular dynamics simulations and free energy calculations, to shed light into the key interaction-based commonalities leading to the dual binding properties of -wrapins for both amyloidogenic proteins, to identify which interactions potentially act as switches diminishing -wrapins' binding activity for A/-syn, and to examine the binding properties of the current most potent -wrapin for A. Our analysis provides insights into the distinct role of the key determinants leading to -wrapin binding to A and -syn, and suggests that the A 18VFFAED23 and -syn 38LYVGSK43 are key domains determining the binding specificity of a -wrapin. Our findings can potentially lead to the discovery of novel therapeutics for Alzheimer's and Parkinson's diseases.
