Evolution of large Aβ16–22 aggregates at atomic details and potential of mean force associated to peptide unbinding and fragmentation events

Abstract

Atomic characterization of large nonfibrillar aggregates of amyloid polypeptides cannot be determined by experimental means. Starting from β-rich aggregates of Y and elongated topologies predicted by coarse-grained simulations and consisting of more than 100 Aβ16-22 peptides, we performed atomistic molecular dynamics (MD), replica exchange with solute scaling (REST2), and umbrella sampling simulations using the CHARMM36m force field in explicit solvent. Here, we explored the dynamics within 3 μs, the free energy landscape, and the potential of mean force associated with either the unbinding of one single peptide in different configurations within the aggregate or fragmentation events of a large number of peptides. Within the time scale of MD and REST2, we find that the aggregates experience slow global conformational plasticity, and remain essentially random coil though we observe slow betastrand structuring with a dominance of antiparallel beta-sheets over parallel betasheets. Enhanced REST2 simulation is able to capture fragmentation events, and the free energy of fragmentation of a large block of peptides is found to be similar to the free energy associated with fibril depolymerization by one chain for longer Aβ sequences.

A brief history of amyloid aggregation simulations

“…Aggregates involving more than 100 of Aβ 16À22 that formed in these CG simulations were then further studied at the all-atom level using REMD simulations, which revealed slow β-strand structuring with a dominance of antiparallel over parallel β-sheets. 184 In 2019, similar results were reported when OPEP was combined with hydrodynamic interactions in an offlattice approach. 185 This approach primarily sampled elongated aggregates formed through a two-step nucleation mechanism, where initially disordered aggregates fused to elongate the amorphous prefibrillar aggregates.…”

“…Their findings demonstrated that hydrodynamic interactions significantly influenced the aggregation process by causing fluctuations in oligomer sizes due to the fusion and fission of aggregates. Aggregates involving more than 100 of $$$ {\mathrm{A}\upbeta}_{16-22} $$$ that formed in these CG simulations were then further studied at the all‐atom level using REMD simulations, which revealed slow β‐strand structuring with a dominance of antiparallel over parallel β‐sheets 184 . In 2019, similar results were reported when OPEP was combined with hydrodynamic interactions in an off‐lattice approach 185 .…”

Multistep molecular mechanisms of Aβ16-22 fibril formation revealed by lattice Monte Carlo simulations

“…Cluster C7 is consistent with the low β-signal during the lag phase observed by means of experiments 9 and MD and REST2 simulations. 42 We never trapped stable oligomers of small sizes with β-sheet (cluster C2)…”

“…35 Molecular simulations on large oligomers showed that Aβ16-22 formed metastable well-structured βbarrels and perpendicular β-sheets. [36][37][38] Overall, the experimental times for primary nucleation and secondary nucleation composed of fragmentation and surface-catalysed effects 39,40 replica exchange with solute tempering, 41,42 metadynamics, 43,44 and path sampling 31 with different protein representations and force fields were used to overcome the free energy barriers involved in each microscopic event. However, metadynamics efficiency depends on the definition of collective variables, path sampling technique depends on the order parameters, and the number of replicas used in REMD increases substantially with the number of degrees of freedom.…”

Peptide Self-Assembly into Amyloid Fibrils: Unbiased All-Atom Simulations

“…Therefore, the search for complex order parameters may become an intensive area of research in the theoretical physical chemistry community. Although this perspective focuses on unbiased all-atom simulations, we would be remiss not to mention the important role played by coarse-grained simulations in describing phenomena taking place at longer and larger length scales − or the role played by alpha-fold . It is also anticipated that our understanding of amyloid aggregation will be significantly improved by studying longer model peptides, which exhibit β-arcs in the fibril state, see Figure e.…”