Emergence of Barrel Motif in Amyloid-β Trimer: A Computational Study

Abstract

Amyloid-β (Aβ) peptides form assemblies that are pathological hallmarks of Alzheimer's disease. Aβ oligomers are soluble, mobile, and toxic forms of the peptide that act in the extracellular space before assembling into protofibrils and fibrils. Therefore, oligomers play an important role in the mechanism of Alzheimer's disease. Since it is difficult to determine by experiment the atomic structures of oligomers, which accumulate fast and are polymorphic, computer simulation is a useful tool to investigate elusive oligomers' structures. In this work, we report extended all-atom molecular dynamics simulations, both canonical and replica exchange, of Aβ(1−42) trimer starting from two different initial conformations: (i) the pose produced by the best docking of a monomer aside of a dimer (simulation 1), representing oligomers freshly formed by assembling monomers, and (ii) a configuration extracted from an experimental mature fibril structure (simulation 2), representing settled oligomers in equilibrium with extended fibrils. We showed that in simulation 1, regions with small β-barrels are populated, indicating the chance of spontaneous formation of domains resembling channel-like structures. These structural domains are alternative to those more representative of mature fibrils (simulation 2), the latter showing a stable bundle of C-termini that is not sampled in simulation 1. Moreover, trimer of Aβ(1−42) can form internal pores that are large enough to be accessed by water molecules and Ca 2+ ions.

Nanomechanical Stability of Aβ Tetramers and Fibril-like Structures: Molecular Dynamics Simulations

“…The pulling work is computed by the following equation: All systems were simulated with the TIP3P water model and CHARMM36m force field, which was developed for intrinsically disordered proteins such as Aβ peptides. Indeed, this force field has been validated in previous studies of Aβ 42 monomers and oligomers . The GROMACS package, ver.…”

“…Indeed, this force field has been validated in previous studies of Aβ 42 monomers 19 and oligomers. 20 The GROMACS package, ver. 5.1.2, 31 was the molecular dynamics engine.…”

“…However, the structure of small oligomers cannot be resolved experimentally due to their transient nature that comes from fast aggregation in solution. In this situation MD simulations were used to obtain their structures. ,− …”

Amyloid β Dodecamer Disrupts the Neuronal Membrane More Strongly than the Mature Fibril: Understanding the Role of Oligomers in Neurotoxicity

“… 40 , 41 A different neuronal membrane model was used to study the dimerization of Aβ42 near the membrane using MD simulations. 42 In this work, we also used all-atom MD simulations, as they were successful in characterizing Aβ monomers and low-weight oligomers in solution 43 − 45 and on the membrane surface. 31 , 32 We studied three systems, including pure membrane without Aβ, membrane–dodecamer complex, and membrane–fibril complex.…”

“…Ganglioside GM1 can have an impact on Aβ fibrillogenesis and membrane disruption, , while the cholesterol level affects the production and pore formation of Aβ in membranes. − Therefore, we used a more realistic neuronal membrane model which is called the disease 1 (D1) model introduced by Drolle et al This model is composed of DPPC, POPC, sphingomyelin (SM), cholesterol, and ganglioside GM1, which are found in the outer leaflet of neuronal cell membranes. , A different neuronal membrane model was used to study the dimerization of Aβ42 near the membrane using MD simulations . In this work, we also used all-atom MD simulations, as they were successful in characterizing Aβ monomers and low-weight oligomers in solution − and on the membrane surface. , We studied three systems, including pure membrane without Aβ, membrane–dodecamer complex, and membrane–fibril complex.…”