(231f) Amyloid Fibrillization Mystery: Is Backtracking Real?
AIChE Annual Meeting
2019
2019 AIChE Annual Meeting
Engineering Sciences and Fundamentals
Thermodynamics of Biomolecular Folding and Assembly
Monday, November 11, 2019 - 4:45pm to 5:00pm
Amyloid-Beta (Aβ) is a peptide that forms fibrils and senile plaques found in the brains of
patients with Alzheimer’s disease (AD). Recent evidence suggests that soluble oligomeric species
and specific polymorphs of the mature fibrils might constitute the neurotoxic species
responsible for neuron damages. Although a wide range of Aβ oligomers and fibrils structures
have been studied on different levels, numerous fundamental questions of the aggregation of the
Aβ peptides into oligomers and plaques remain unanswered. To elucidate the nature of the
transition state for incorporation of Aβ monomers into fibrils, we monitor the growth Aβ fibrils
at various concentrations of Aβ peptide and urea by time-resolved in situ atomic force
microscopy. We determine the concentration at which the fibrils are in equilibrium with
peptides, i.e., the solubility, and the rate constant for fibril growth as functions of urea
concentration. Our experiments reveal that urea increases both the solubility of Aβ peptide and
the growth rate of the fibrils. The behavior contradicts the common notion that higher solubility,
implying lower fibril stability, correlates with slower growth rate. We attribute this
counterintuitive behavior to the presence of an activated complex, in which a monomer is
nonspecifically bound to the fibril tip before transforming to the next growth-competent fibril
tip configuration. The non-specific contacts between the backbones of the incoming and
terminal fibril monomers contribute to the transition-state free energy. Urea, which favors the
backbones of both monomers, prevents such contacts and lowers . A similar scenario observed
during protein folding has been referred to as backtracking. We carried out numerical
simulations employing predictive coarse-grained protein force field (associative memory, water-
mediated, structure, and energy model, AWSEM) with atomic-level MD simulations of select
configurations along the reaction coordinate for association of a monomer to the fibril end. The
model results reproduce the unusual correlation between the urea effects on the fibril stability
and its rate of growth and support the conclusion of the significance of a transition state based
on non-native prematurely formed contracts between the fibril end and a docked monomer.
patients with Alzheimer’s disease (AD). Recent evidence suggests that soluble oligomeric species
and specific polymorphs of the mature fibrils might constitute the neurotoxic species
responsible for neuron damages. Although a wide range of Aβ oligomers and fibrils structures
have been studied on different levels, numerous fundamental questions of the aggregation of the
Aβ peptides into oligomers and plaques remain unanswered. To elucidate the nature of the
transition state for incorporation of Aβ monomers into fibrils, we monitor the growth Aβ fibrils
at various concentrations of Aβ peptide and urea by time-resolved in situ atomic force
microscopy. We determine the concentration at which the fibrils are in equilibrium with
peptides, i.e., the solubility, and the rate constant for fibril growth as functions of urea
concentration. Our experiments reveal that urea increases both the solubility of Aβ peptide and
the growth rate of the fibrils. The behavior contradicts the common notion that higher solubility,
implying lower fibril stability, correlates with slower growth rate. We attribute this
counterintuitive behavior to the presence of an activated complex, in which a monomer is
nonspecifically bound to the fibril tip before transforming to the next growth-competent fibril
tip configuration. The non-specific contacts between the backbones of the incoming and
terminal fibril monomers contribute to the transition-state free energy. Urea, which favors the
backbones of both monomers, prevents such contacts and lowers . A similar scenario observed
during protein folding has been referred to as backtracking. We carried out numerical
simulations employing predictive coarse-grained protein force field (associative memory, water-
mediated, structure, and energy model, AWSEM) with atomic-level MD simulations of select
configurations along the reaction coordinate for association of a monomer to the fibril end. The
model results reproduce the unusual correlation between the urea effects on the fibril stability
and its rate of growth and support the conclusion of the significance of a transition state based
on non-native prematurely formed contracts between the fibril end and a docked monomer.