Exploration of the Phase Field Framework Marmot To

Butterfield, Aaron

doi:10.2172/1093887

Cited by 1 publication

(1 citation statement)

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“…17 Two other proposed mechanisms involve the association of Aβ42 with cell membranes, causing thinning and subsequent leakage of small molecules. 18,19 All depend highly on the interaction of Aβ42 with cell membranes, indicating the importance of detailed understanding of the propensity of Aβ42 to adhere to and aggregate on various surfaces as well as the driving forces behind such behavior. Moreover, elucidating the effect of various surfaces on the kinetics and mechanism of monomer association with a preformed fibril may inform new therapeutic methods for inhibiting this process.…”

Section: Introductionmentioning

confidence: 99%

Amyloid-β (Aβ42) Peptide Aggregation Rate and Mechanism on Surfaces with Widely Varied Properties: Insights from Brownian Dynamics Simulations

2020

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Amyloid-β (Aβ) plaques, which form by aggregation of harmless Aβ peptide monomers into larger fibrils, are characteristic of neurodegenerative disorders such as Alzheimer's disease. Efforts to treat Alzheimer's disease focus on stopping or reversing the aggregation process that leads to fibril formation. However, effective treatments are elusive due to certain unknown aspects of the process. Many hypotheses point to disruption of cell membranes by adsorbed Aβ monomers or oligomers, but how Aβ behaves and aggregates on surfaces of widely varying properties, such as those present in a cell, is unclear. Elucidating the effects of various surfaces on the dynamics of Aβ and the kinetics of the aggregation process from bulk solution to a surface-adsorbed multimer can help identify what drives aggregation, leading to new methods of intervention by inhibitory drugs or other means. In this work, we used all-atom Brownian dynamics simulations to study the association of two distinct Aβ42 monomer conformations with a surface-adsorbed or free-floating Aβ42 dimer. We calculated the association time, surface interaction energy, surface diffusion coefficient, surface residence time, and the mechanism of association on four different surfaces and two different bulk solution scenarios. In the presence of a surface, the majority of monomers underwent a two-dimensional surface-mediated association that depended primarily on an Aβ42 electrostatic interaction with the self-assembled monolayer (SAM) surfaces. Moreover, aggregation could be inhibited greatly by surfaces with high affinity for Aβ42 and heterogeneous charge distribution. Our results can be used to identify new opportunities for disrupting or reversing the Aβ42 aggregation process.

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Section: Introductionmentioning

confidence: 99%