Summary
The kinetics of aggregation typically follow a sigmoidal curve characterized by a rate-limiting lag phase (primary nucleation), an exponential growth phase, and a plateau phase. Secondary nucleation on fibril surfaces is critical for toxic oligomer generation.
Key Points
- 1Aggregation follows sigmoidal kinetics with lag, growth, and plateau phases
- 2Secondary nucleation on fibrils generates toxic oligomers
- 3Seeding eliminates the lag phase
- 4Targeting secondary nucleation is key therapeutic strategy
Understanding the kinetics of protein aggregation is essential for developing therapeutic strategies against amyloid diseases.
The Sigmoidal Kinetic Profile
Amyloid formation characteristically follows a sigmoidal (S-shaped) curve:
Lag Phase
- Primary nucleation: Slow, thermodynamically unfavorable
Growth Phase
- Elongation: Monomers add to fibril ends
- Secondary nucleation: New nuclei form on fibril surfaces
Plateau Phase
Microscopic Processes
Modern kinetic analysis distinguishes multiple microscopic steps:
Primary Nucleation
Elongation
Secondary Nucleation
This is the critical insight of modern kinetic theory:
- Creates autocatalytic amplification
Fragmentation
Therapeutic Implications
Different kinetic stages offer different intervention points:
1. Native state stabilizers: Prevent initial unfolding (e.g., Tafamidis)
2. Primary nucleation inhibitors: Extend lag phase
3. Secondary nucleation inhibitors: Reduce oligomer production
4. Elongation inhibitors: Cap fibril ends
5. Fibril breakers: Destabilize cross-β structure