Molecular Mechanisms of Lipid-Induced Amyloid Fibril Formation from Global Fitting of Kinetic Models.

Elucidating the molecular mechanisms of amyloid fibril aggregation from soluble peptides is central

to building an understanding and the potential control of protein aggregation disorders, such as

Alzheimer's and Parkinson's diseases. A fundamental challenge in achieving this is the complexity of

the aggregation reaction network itself, which makes it difficult to analyse kinetic data of protein

aggregation in terms of the underlying mechanisms. Here we present a theoretical framework, based

on chemical reaction kinetics and global fitting, that allows the interpretation of quantitative

experimental measurements of α-synuclein aggregation on lipid membranes, a process linked to

Parkinson’s disease. These results provide a framework for modelling amyloid forming systems with

lipid-dependent interactions and has the potential to guide the rational design of small-molecule

inhibitors of α-synuclein aggregation.