  Probing the reaction mechanisms of supramolecular processes in soft- and
biological matter, such as protein aggregation, is inherently challenging.
These processes emerge from the simultaneous action of multiple molecular
mechanisms, each of which is associated with the rearrangement of a large
number of weak bonds, resulting in a complex free energy landscape with many
kinetic barriers. Reaction rate measurements of supramolecular processes at
different temperatures can offer unprecedented insights into the underlying
molecular mechanisms and their thermodynamic properties. However, to be able to
interpret such measurements in terms of the underlying microscopic mechanisms,
a key challenge is to establish which properties of the complex free energy
landscapes are probed by the reaction rate. Here, we present a reaction rate
theory for supramolecular kinetics based on Kramers rate theory for diffusive
reactions over multiple kinetic barriers, and apply the results to protein
aggregation. Using this framework and Monte Carlo simulations, we show that
reaction rates for protein aggregation are of the Arrhenius-Eyring type and
that the associated activation energies probe only one relevant barrier along
the respective free energy landscapes. We apply this advancement to interpret,
both in experiments and in coarse-grained computer simulations, reaction rate
measurements of amyloid aggregation kinetics in terms of the underlying
molecular mechanisms and associated thermodynamic signatures. Our results
establish a general platform for probing the mechanisms and energetics of
supramolecular phenomena in soft- and biological matter using the framework of
chemical kinetics.
