Conformational Selection of α-Synuclein Tetramers at Biological Interfaces.

Controlling the polymorphic assemblies of α-synuclein (αS) oligomers is crucial to reroute toxic protein aggregation implicated in Parkinson's disease (PD). One potential mediator is the interaction of αS tetramers with cell membranes, which may regulate the dynamic balance between aggregation-prone disordered monomers and aggregation-resistant helical tetramers. Here, we model diverse tetramer-cell interactions and compare the structure-function relations at the supramolecular-biological interface with available experimental data. The models predict preferential interaction of compact αS tetramers with highly charged membrane surfaces, which may further stabilize this aggregation-resistant conformer. On moderately charged membranes, extended structures are preferred. In addition to surface charge, curvature influences tetramer thermodynamic stability and aggregation, with potential for selective isolation of tetramers via regio-specific interactions with strongly negatively charged micelles that screen further aggregation. Our modeling data set highlights diverse beneficial nano-bio interactions to redirect biomolecule assembly, supporting new therapeutic approaches for PD based on lipid-mediated conformational selection and inhibition.