Amyloid assembly is dominated by misregistered kinetic traps on an unbiased energy landscape

Abstract

Atomistic description of protein fibril formation has been elusive due to the complexity and long time scales of the conformational search. Here, we develop a multiscale approach combining numerous atomistic simulations in explicit solvent to construct Markov State Models (MSMs) of fibril growth. The search for the in-register fully bound fibril state is modeled as a random walk on a rugged two-dimensional energy landscape defined by β-sheet alignment and hydrogen-bonding states, whereas transitions involving states without hydrogen bonds are derived from kinetic clustering. The reversible association/dissociation of an incoming peptide and overall growth kinetics are then computed from MSM simulations. This approach is applied to derive a parameter-free, comprehensive description of fibril elongation of Aβ16–22 and how it is modulated by phenylalanine-to-cyclohexylalanine (CHA) mutations. The trajectories show an aggregation mechanism in which the peptide spends most of its time trapped in misregistered β-sheet states connected by weakly bound states twith short lifetimes. Our results recapitulate the experimental observation that mutants CHA19 and CHA1920 accelerate fibril elongation but have a relatively minor effect on the critical concentration for fibril growth. Importantly, the kinetic consequences of mutations arise from cumulative effects of perturbing the network of productive and nonproductive pathways of fibril growth. This is consistent with the expectation that nonfunctional states will not have evolved efficient folding pathways and, therefore, will require a random search of configuration space. This study highlights the importance of describing the complete energy landscape when studying the elongation mechanism and kinetics of protein fibrils.

Insight Into Seeded Tau Fibril Growth From Molecular Dynamics Simulation of the Alzheimer’s Disease Protofibril Core

“…As seen in Figure 3 (black line), after the wild-type tau makes initial contact with the PHF fibril at around 8 nm, the FES exhibits a docking region without a steep folding funnel. This feature agrees with recent models of amyloid aggregation progressing via a random search through multiple, non-productive conformations before the peptide samples an extended configuration that is able to form native contacts with the fibril template ( Jia et al, 2017 ; Jia et al, 2020 ). In contrast, phosphorylation at Ser356 shifts the conformational ensemble towards more extended conformations ( Figure 4 ), and the FES in Figure 3 (green line) exhibits a steeper folding funnel, along which native contacts form in successive order along the fibril template.…”

Secondary Nucleation and the Conservation of Structural Characteristics of Amyloid Fibril Strains

“…However, the fact that fibril elongation rates saturate at high monomer concentration (Buell, 2019) indicates that elongation involves more than a single molecular step. It probably involves an initial weak association between the monomer and the seed fibril end, followed by a conformational search for the thermodynamically most stable state (Jia et al, 2020). Sometimes the fibril end can remain in a state in which the last incoming monomer has not yet reached the correct structure for extended periods of time, as suggested by the fibril's inability to grow further during this time period, i.e., stopand-go-kinetics of fibril growth (Ferkinghoff-Borg et al, 2010).…”

Aggregation of Aβ40/42 chains in the presence of cyclic neuropeptides investigated by molecular dynamics simulations

“…Within the time regimes of the present MD study, this results in a prevalence of multiple small Aβ 42 aggregates. The resulting delay in hydrophobicity-driven coalescence may explain the extended lag phase of Aβ 42 aggregation observed experimentally [22]. In contrast, AVP molecules preferentially bind to central regions of Aβ 42 peptides, and are prone to develop extensive inter-species hydrogen bonding.…”

“…The toxicity of non-fibrillary and pre-fibrillary oligomeric assemblies has been hypothetically linked to the exposure of hydrophobic groups and unpaired β-strands at their surfaces [ 9 , 20 ], often referred to as a “sticky surface” effect. Recent modeling studies [ 21 , 22 ] indicate that accumulation of subtle structural perturbations of early aggregates at the onset of the oligomerization process may result in distinct aggregation pathways at later, more advanced stages of Aβ oligomerization. Altogether, both experimental and theoretical evidence suggests that molecular events occurring early in the process of aggregation play a key role in determining both the structure and toxicity of Aβ oligomers [ 14 ].…”