Mechanisms and Kinetics of Amyloid Aggregation Investigated by a Phenomenological Coarse-Grained Model - Computational Modeling of Biological Systems - page 200

20, N pf
la

100, N pf (white nodes, N la

la D 4)
are the most populated states during the lag phase and the final equilibrium,
respectively. Strikingly, a greater variety of aggregation mechanisms emerges for
the poorly amyloidogenic CGF peptide model (see Fig. 7 , bottom) than the highly
amyloidogenic CGF peptide model (see Fig. 7 , top). Indeed, the former shows the
presence of intermediates, i.e., protofibrils consisting of only two (green nodes)
or three (blue nodes) protofilaments. According to this analysis, it is reasonable
to expect that a mutation that decreases the ˇ-aggregation tendency could result
in a greater variety of prefibrillar aggregates, as in the case of the Arctic mutant
(E22G) of the Alzheimer's Aˇ peptide and the A30P mutant for ˛-synuclein, for
which a more pronounced in vitro formation of oligomers and protofibrils was
observed. [ 51 , 52 ]

D 0) and fibrils (red nodes, N la

4.2 Mechanism of Nucleation

The nucleation properties of the CGF model are investigated by evaluating the
probability of fibril formation for ˇ-subdomains, i.e., the clusters of interacting
ˇ-monomers. The nucleus, defined as the oligomer containing a ˇ-subdomain with a
50% probability to form a fibril, shows an increasing size upon destabilization of the
ˇ-state. Significantly different nucleation mechanisms are observed upon variation
of the amyloidogenicity parameter dE (Fig. 8 ). For high values of the amyloido-
genic propensity (

0.0 kcal/mol), the nucleus size is submicellar, and
nucleation is simply the aggregation of monomers in the ˇ-state. On the contrary, for
poorly amyloidogenic peptides, nucleus formation requires either spatial proximity
of several monomers in the ˇ-state (dE D 2:25 kcal/mol) within a micelle or
collision of two peptide micelles with merging of their ˇ-subdomains (dE D
2:5 kcal/mol). The variety of aggregation scenarios is also observed experimentally.
An unstructured peptide with a marginally stable ˇ-prone state like Aˇ 40 [ 53 , 54 ]
visits oligomeric intermediates in the lag phase, and has a very weak dependence
of the elongation rate on concentration due to the monomer-micelle equilibrium.
This mechanism corresponds to the nucleated conformational conversion proposed
by Serio et al. [ 55 ] On the other hand, a functional and nonpathological amyloid
in mammalians [ 56 ] lacks on-pathway intermediates and corresponds to the highly
amyloidogenic CGF peptide model. Once more, by varying the only free parameter
dE of the CGF model, it is possible to describe the aggregation properties of a wide
and diverse range of (poly)peptide sequences.

2:0 dE

4.3 Concentration Effects

The dE parameter of the CGF model has a strong influence on the concentration
dependence of the fibril-formation kinetics. In agreement with the above-mentioned
mechanism of nucleation, CGF peptides poorly prone to aggregation nucleate only