Biomedical Engineering Reference
In-Depth Information
Fig. 4
Influence of amyloidogenic tendency on aggregation kinetics. (
Left
): Time series of the
fraction of ordered aggregation evaluated at four values of the amyloidogenic tendency, from
very prone to form fibrillar aggregates (dE
D
0:0 kcal/mol) to marginal propensity (dE
D
2.5 kcal/mol). Ten independent simulations are shown for each dE value. (
Right
): Fluorescence
intensity (degree of aggregation) of V18I (
a
), V18Q (
b
), and V18P (
c
) mutants of Aˇ
40
[
48
].
Note that the ns-s timescales in the CGF model simulations are much shorter than in the
experiments (hours) because of the much higher concentration in the former (8.5 mM) than in
the latter (120 M). Reprinted from [
37
](
left
)and[
48
](
right
) with permission by Elsevier (
left
)
and Jon Wiley & Sons (
right
)
values of the amyloidogenic propensity dE. The extent of aggregation is controlled
by counting the number of polar contacts: a polar contact is formed whenever two
dipoles of different monomers are closer than 5 A. Three different kinetic phases are
visible: lag, elongation, and final monomer-fibril equilibrium. The variable length
of the lag phase and the higher heterogeneity at longer lag times are indicative of
a stochastic nucleation [
47
]. Fibril formation is much slower for the ˇ-unstable
models (dE
1.0
and 0.0 kcal/mol). Both the lag phase and the elongation kinetics are affected
by the single free parameter dE of the CGF model. Interestingly, the kinetics
of aggregation are qualitatively consistent with the experimental data on single-
D
2.5 and
2.25 kcal/mol) than the ˇ-stable models (dE
D
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