Huntingtin exon-1 fragments carrying an expanded CAG-repeat tract misfold into a polyglutamine (polyQ) β-sheet ("polar zipper") and self-assemble by nucleated polymerization — the same two-step kinetic scheme used for amyloid-β and other amyloidogenic proteins:
1) Nucleation (slow, rate-limiting):
n* monomers → 1 nucleus rate k_n(Q)
2) Elongation (fast, diffusion-limited):
nucleus + monomer → nucleus(+1) rate k_e
The nucleation rate is strongly, non-linearly length-dependent — the mechanistic basis of the CAG-repeat pathogenic threshold seen in Huntington's disease (onset accelerates sharply above ~36–39 repeats):
k_n(Q) = k0 · exp[ α (Q − Qc) ]
Qc ≈ 36 repeats (pathogenic threshold)
- CAG repeat length Q — sets k_n(Q). Below ~Qc almost no nuclei form in the simulated window; each ~4 repeats above it multiplies the nucleation rate several-fold, exactly the steep length-dependence measured for huntingtin exon-1 aggregation kinetics in vitro.
- Monomer pool size — starting free-monomer concentration; higher concentration raises encounter frequency for both nucleation and elongation.
- Diffusion rate D — Brownian-motion speed of free monomers (temperature/viscosity proxy); faster diffusion raises the encounter rate for both steps.
- Critical nucleus size n* — how many monomers must transiently cluster to seed a stable fibril. A larger n* makes nucleation rarer (higher kinetic order in monomer concentration) but, once formed, growth is unaffected.
Once a nucleus exists it acts as a template: free monomers captured within its docking radius add irreversibly to the growing end, producing the beaded chain — a simplified stand-in for ordered cross-β stacking along a fibril axis. This nucleation-elongation model (Perutz 1994; Chen, Berthelier, Wetzel et al., PNAS 2002) explains both the sigmoidal aggregation kinetics seen in thioflavin-T assays and why polyQ length is the dominant determinant of aggregation propensity and disease onset.