Alberto Coden

Amyloid fibrils are highly stable misfolded protein assemblies playing an important role in several neurodegenerative and systemic diseases. While structural information of the amyloid state is now abundant, mechanistic details about the misfolding process remain elusive. Here we present a Φ-value inspired approach and apply it to PI3K-SH3 amyloid fibrils to examine the rate-limiting step for fibril elongation. We use experimental Φvalues as constraints in biased MD-simulations to provide the first view of the transition state of a protein misfolding reaction. The resulting framework is generally applicaple and provides mechanistic insight into the misfolding reaction comparable to the breakthroughs previously achieved for protein folding. While protein folding proceeds on funnel-shaped landscapes, we find that the misfolding reaction energy landscape consists of a large ’golf course’ region, defined by a single energy barrier and transition state, accessing a sharply funneled region. Thus, misfolding occurs by numerous unsuccesful binding attempts and rare successful monomer-fibril end collisions which rapidly anneals to the final state. Taken together, these insights enable, the first quantitative and highly resolved description of a protein misfolding reaction.