Figure 11.

A conjectural plot of the free energy, G, for conversion of native protein, I_n (dimer at pH 1.6 and 65±2°C), to unfolded protein, I_u, to nuclei, N, to oligomers, O, and then to amyloid fibrils, F. The proposed reactions are as folows: (i) For the initial reaction without added seed oligomers or fibers (control)

$$I_n\iff I_u\iff N\to O\stackrel{+N}{\to }F.$$ (5)

(ii) With added seed oligomers (no fibers added)

$$I_n\iff I_u\stackrel{+O}{\to }O\to F$$ (6)

(iii) With added seed fibers (no oligomers added)

$$I_n\iff I_u\stackrel{+F}{\to }F$$ (7)

A four-step, three-step and two step barrier process is proposed for reactions (5), (6) and (7), repsectively. The transiion state energy for each step of the control reaction (Eq. (5)) is ΔG_i^# where i = u, N, O and F to form the unfolded protein, the nucleus, the oligomer(s) and the fibril species, respectively. Forming the nucleus requires the most energy by far. The process of seeding with oligomers or fibrils obviates the nucleation step and reduces the barrier to fibril formation.