Mechanisms and Kinetics of Amyloid Aggregation Investigated by a Phenomenological Coarse-Grained Model - Computational Modeling of Biological Systems - page 205

Tabl e 2 Characteristic lag-time of aggregation t 50 for CGF peptide model for different
amyloidogenic tendency in the presence or absence of lipid vesicles [ 73 ]
Number of

Lag time t 50 [ns]

Scaling of peptide/ runs with with without

lipid interactions Amyloidogenicity fibril formation membrane membrane

0.87 High 10/10 11 ˙ 1 19 ˙ 3

˙ ˙

Interm. 29/29 89 29 56 15

Low 17/20 958 ˙ 503 124 ˙ 28

Very low 0/10 > 2000 318 ˙ 133

0.90 High 10/10 10 ˙ 1 19 ˙ 3

Interm. 30/30 69 ˙ 23 56 ˙ 15

Low 0/20 > 2000 124 ˙ 28

318 ˙ 133 Very low 0/20 > 2000

Values in boldface are significantly larger in the presence of the vesicles

vesicles. As mentioned in section III, peptides with low amyloidogenic potential
can fibrillate only after aggregating into spherical oligomeric intermediates with
hydrophobic interior and hydrophilic surface. In the simulations with lipids, such
oligomeric intermediates form in the bulk but not on the vesicle. Fibrillation of
low amyloidogenic peptides therefore takes place in the bulk and is slower than
in the absence of a vesicle due to the lower effective concentration of peptides in
the solvent. These simulation results are consistent with and explain the apparently
contradictory experimental observations on faster aggregation of the Aˇ [ 68 ]or
˛-synuclein [ 75 ] peptides in the presence of lipid surfaces and slower aggregation
of insulin (which has lower amyloidogenicity), [ 76 ] and have been confirmed by
recent studies on the aggregation properties of human islet amyloid polypeptide
hIAPP 1 19 in presence of lipid vesicles [ 77 ].
To investigate the influence of the CGF peptides on the lipid bilayer, the simu-
lations were initiated with 20 spherical probes inside the vesicle. It was observed
that leakage from the lipid vesicle is enhanced during fibril formation but not by the
mature fibril [ 73 ]. More precisely, a comparison between the fibrillation and probe
release rates (Fig. 11 , left) revealed that probe release is fastest during fibril growth,
whereas the kinetics of probe release in the presence of mature fibrils is as slow as
in the absence of peptides, indicating that mature fibrils do not damage the integrity
of the vesicle. Rather, the ongoing process of aggregation on the vesicle results
in bilayer surface defects. This observation explains why for some amyloidogenic
peptides there exist mutants that form fibrils more rapidly and are more toxic
than the wild-type peptides, even though their fibrils are not toxic. [ 78 ]Moreover,
these computational results are in agreement with the experiments performed by
Engel et al. on membrane damage caused by human islet amyloid polypeptide
(hIAPP) fibril growth [ 69 ](Fig. 11 right).
It has also been hypothesized that formation of toxic oligomers that induce
membrane leakage could be the result of a backward production of oligomers from
the mature fibril. [ 79 ] Interestingly, by modulating the attraction between the CGF