Fig. 8.

Concerted reaction scheme for AS progression from monomeric to fibrillar structures. Stippled blue domain: pre-amyloid manifold; stippled red domain: amyloid manifold. Clusters are associated oligomeric species. Fuzzy is an associated form of AS (see ESM) created on the surface of colloid [catalytic function denoted by italics and small blue rectangle) with a rate constant k3 (colloid)] and released, progressing via spontaneous conformational transition (k5) to an amyloid nucleus that is absorbed into the fibrillation cycle by end addition of monomer (k7). The formation of clusters, colloid, fuzzy, and nucleus are considered as concerted and assigned n1, n2, p, and p monomers units, respectively in the kinetic equations (ESM). A redistribution between supramolecular forms in the fuzzy compartment is not featured explicitly. Fibrils undergo autocatalytic expansion (k8, circle) involving secondary nucleation and fragmentation (not indicated). A potential parallel amyloid nucleation path involves fuzzy-catalyzed conversion of clusters to nucleus (k9) and conceivably (not shown) other supramolecular species. Clusters can also function as a monomer “reservoir, buffer”. Additional details are given in the ESM