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

Abstract

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.

Effect of Surface Roughness on Aggregation of Polypeptide Chains: A Monte Carlo Study

“…Protein aggregation can occur in solution as well as in complex environments, including various surrounding objects such as cell membranes, DNA, sugars, other biological compounds and industrial artificial surfaces which require the careful study of the effect of different surfaces on the process [4][5][6][7][8]. In general, the impact of foreign surfaces on the protein aggregation process displays complicated behaviors which depend on the type of surfaces, proteins and experiment conditions [9][10][11][12]. Lipid membranes were reported to play the role of a template to accelerate the aggregation of different amyloidogenic peptides [13][14][15][16].…”

Modeling Effects of Surface Properties and Probe Density for Nanoscale Biosensor Design: A Case Study of DNA Hybridization near Surfaces

“…Notably, this higher 2D fraction corresponds with slightly faster hybridization times for the 0.001 and 0.002 nm –2 probe densities on this surface compared to the OH-SAM (Table ), indicating that hybridization time was decreased by the high surface concentration of targets. This increased molecular association rate due to reduced search dimensionality has been demonstrated elsewhere both computationally and experimentally for other biomolecules so long as desorption from the surface is not impeded by attractive forces. Indeed, striking a balance between attractive forces that shuttle targets to a surface and subsequently to the probes, while allowing rapid 2D diffusion and desorption from the surface, is the key factor if the goal is to expedite association kinetics.…”

“…This can play an explanatory role by systematically varying certain system properties or can be used to guide design toward optimal function. For example, simulation has been successfully used on its own and in conjunction with experimentation to elucidate SAM interactions with proteins, , surface-bound receptors, biosensor dynamics, and protein–ligand interactions. , One important question concerns the amount of two-dimensional (2D) hybridization, that is, surface-mediated diffusion of target DNA along the SAM leading to hybridization, versus the amount of three-dimensional (3D) hybridization, in which hybridization occurs by diffusion of targets through the solvent directly to probes. This property is relevant in many fields; genotyping and gene expression profiling take advantage of DNA microarrays utilizing special surfaces, , and catalysis may utilize surfaces with immobilized catalysts to enhance reaction rates .…”

Molecular Mechanics Study of Flow and Surface Influence in Ligand–Protein Association

“…The average association time did not differ without or with SAM in the presence of diffusion flux ( Table 3 ). This is not surprising because the CH 3 -SAM provides only weak attractions to xk263, and the surface neither increased the local concentration of xk263 to assist ligand association nor retained the ligand from binding to HIVp ( Figure 6 ) (Cholko et al, 2020 ). However, if the attraction between a ligand and surface is large, it may affect experimental results.…”