Molecular Dynamics Simulations of Amyloid β -Peptide (1-42): Tetramer Formation and Membrane Interactions

Abstract

The aggregation cascade and peptide-membrane interactions of the amyloid β-peptide (Aβ) have been implicated as toxic events in the development and progression of Alzheimer's disease. Aβ42 forms oligomers and ultimately plaques, and it has been hypothesized that these oligomeric species are the main toxic species contributing to neuronal cell death. To better understand oligomerization events and subsequent oligomer-membrane interactions of Aβ42, we performed atomistic molecular-dynamics (MD) simulations to characterize both interpeptide interactions and perturbation of model membranes by the peptides. MD simulations were utilized to first show the formation of a tetramer unit by four separate Aβ42 peptides. Aβ42 tetramers adopted an oblate ellipsoid shape and showed a significant increase in β-strand formation in the final tetramer unit relative to the monomers, indicative of on-pathway events for fibril formation. The Aβ42 tetramer unit that formed in the initial simulations was used in subsequent MD simulations in the presence of a pure POPC or cholesterol-rich raft model membrane. Tetramer-membrane simulations resulted in elongation of the tetramer in the presence of both model membranes, with tetramer-raft interactions giving rise to the rearrangement of key hydrophobic regions in the tetramer and the formation of a more rod-like structure indicative of a fibril-seeding aggregate. Membrane perturbation by the tetramer was manifested in the form of more ordered, rigid membranes, with the pure POPC being affected to a greater extent than the raft membrane. These results provide critical atomistic insight into the aggregation pathway of Aβ42 and a putative toxic mechanism in the pathogenesis of Alzheimer's disease.

Atomistic-level study of the interactions between hIAPP protofibrils and membranes: Influence of pH and lipid composition

“…Christensen et al examined the formation process of trimers and tetramers using a highly mobile membrane mimetic model and their simulations showed that initially membrane-bound α-helical hIAPPs can self-assemble into β-sheet structures [42]. Brown et al carried out MD simulations of disordered Aβ1–42 tetramers on zwitterionic lipid bilayers and they observed that the binding of Aβ tetramers on POPC bilayers resulted in a greater membrane perturbation than that on cholesterol-rich membranes [43]. Recently, Dong et al investigated systemically the adsorption dynamics, structural stability and membrane perturbation of protofibrillar Aβ trimers constructed using three different NMR-derived fibril structures, 2BEG, 2LMN and 2M4J.…”

Length‐Dependent Manifestation of Vibration Modes Regulates a Specific Intermediate Morphology of Aβ17‐42 in Different Environments

“…There is a wealth of evidence suggesting that formation and accumulation of Aβ40 and Aβ42 in normal neuronal membranes contributes to Aβ toxicity . It is also known that mature Aβ fibrils are less toxic compared to soluble Aβ oligomers .…”

“…Aβ oligomer intermediates are predominantly composed of β‐sheet structures and are known to trigger Aβ toxicity via several mechanisms . A number of studies have revealed the contributions of Aβ toxic mechanisms to the pathology of AD, including formation of Aβ oligomers promoting the generation of reactive oxygen species, excessive aggregation of Aβ proteins inducing stress in the endoplasmic reticulum, disruption of neuronal cell membrane integrity, and the “amyloid channel hypothesis” that describes the direct insertion of Aβ into membranes, formation of β‐barrel and pore‐like structures,, and disruption of calcium homeostasis …”

Binding of protofibrillar Aβ trimers to lipid bilayer surface enhances Aβ structural stability and causes membrane thinning

“…To get mechanistic insights into membrane disruption by toxic amyloids in atomic detail, several computational groups have investigated the interactions of Aβ oligomers with lipid bilayers by performing molecular dynamics (MD) simulations 41–47 . Jang et al examined the structural properties of modeled Aβ 9–42 /Aβ 17–42 channels in zwitterionic POPC lipid bilayers and obtained Aβ channel conformations with diameters consistent with AFM measurements 41, 48–50 .…”

“…MD simulations by Poojari et al demonstrated that compared to transmembrane Aβ 1–42 monomers, membrane-embedded β-sheet-rich tetramers increased the water flow through the POPC bilayers 44 . Brown et al reported that the binding of disordered Aβ 1–42 tetramers on POPC membranes resulted in a greater membrane perturbation than that on cholesterol-rich membranes 47 . Multiple 80-ns MD simulations by Yu et al showed that the interactions of protofibrillar Aβ 17–42 pentamers with a mixed POPC and POPG membrane are stronger than those with POPC membranes 45 , indicative of the role of surface charge in Aβ-membrane interactions.…”