Fig 9.

Schematic of aggregation pathway. (a) In the absence of heparin both R2/wt and R2/ΔK280 adopt mainly a compact conformation, which is energetically favorable due to presence of both hydrogen bonds and salt bridges. As a consequence, the aggregation is hampered by the necessity of breaking and reforming hydrogen bonds and salt bridges (slow pathway). Coexisting with this compact population is a small population of already extended chains that can undergo a rapid assembly into fibrillar aggregates (fast pathway). (b) Heparin preferentially binds extended conformations, stabilizing them into nucleation prone conformations. By virtue of Le Chatellier’s principle, the overall equilibrium of the unbound chains is driven toward more extended conformations, with the fast pathway now dominating.