Mechanisms and Kinetics of Amyloid Aggregation Investigated by a Phenomenological Coarse-Grained Model - Computational Modeling of Biological Systems - page 210

Tabl e 3 Influence of amyloidogenic propensity on the aggregation kinetics and pathways of the
CGF model [ 37 ]
High amyloidogenicity

Low amyloidogenicity Reference

Small nucleus Large nucleus [37]

Fast fibril formation Slow fibril formation [37]

Downhill Micellar intermediates [37]

No intermediates Protofibrillar intermediates [50]

Single pathway Multiple pathways [50]

Strong concentration dependence Growth rate marginally dependent

on concentration

[37]

Polymorphism under
thermodynamic control

Polymorphism under kinetic control [64]

Can promote membrane leakage Does not promote membrane

leakage

[73]

Slightly accelerated by membranes Decelerated by membranes [73]

Marginally influenced by surfactants Decelerated by surfactants [80]

Not accelerated by macromolecular
crowding

Accelerated by macromolecular
crowding

[81]

Phe-Phe, GNNQQNY, transthyretin,
Aˇ 42

Aˇ 40 , Sup35, prion protein,
myoglobin

-

The last line lists some examples but it must be stressed that amyloidogenic tendency strongly
depends on external conditions, so that the same polypeptide sequence can show drastically
different amyloidogenic tendency depending on pH, temperature, etc.

and solvent-induced conformational changes, by which it is not possible to decouple
changes in intra- from intermolecular interactions.
In conclusion, a slight modification of the free energy profile of an extremely
simplified model of an amphipathic peptide is sufficient to observe a wide range
of different fibril formation mechanisms, providing a unifying description of the
heterogeneity of the experimentally observed kinetics of amyloid fibril formation.

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