Simulation Study on Complex Conformations of Aβ₄₂ Peptides on a GM1 Ganglioside-Containing Lipid Membrane

Abstract

Aggregation and complex formation of amyloid beta (Aβ) peptides on a neuronal cell membrane is a hallmark of neuro-disturbance diseases. In this work, we performed molecular dynamics (MD) simulations to investigate the initial stage of interactions of multiple Aβ 42 peptides on a GM1 ganglioside-containing membrane that mimics a micro-domain on the neuronal cell surface. Conformational changes of Aβs due to adhesion on the membrane and subsequent molecular interactions among the Aβs were monitored. It was suggested from results of the two 1.0 µs simulation trials that stable complexes of Aβ peptides were not rapidly generated but that a steady binding of two Aβs was gradually formed. Observation of two Aβs that will be a complex with steady binding revealed that one Aβ was bound to the membrane surface, while the other was attached to the first one without strong contact with the membrane. The motion of the first one was restricted and its conformational change was limited, with the basic side-chains of Arg5 and Lys28 working as anchors to hold the Aβ helix region on the membrane. In contrast, the second one had high flexibility and showed diversity in its conformation. The second Aβ can search for an energetically favorable binding position on the first one. A parallel β-sheet structure was formed between the C-terminal sides of the two Aβs. Ala30 was critically important to lead the stable β-sheet conformation at the C-terminal hydrophobic domains of Aβs. In the N-terminal sides, helix structures were kept in both Aβs.Key words amyloid beta peptide; molecular dynamics simulation; membrane surface; molecular interaction; conformational change; complex structure Aggregation of amyloid beta (Aβ)-peptides is closely linked to several neurodegeneration diseases including Alzheimer's disease (AD).1-3) Aβ is a small peptide consisting of typically 39-43 amino acid residues and it is a normal product of cellular metabolism from amyloid precursor protein (APP) due to the successive proteolytic action by β-and γ-secretases. 4,5) Aggregation and resultant transformation of Aβ peptides into insoluble misfolding proteins is a pathological hallmark of neurodegeneration diseases in the brain.4) The most commonly observed forms of toxic Aβs are comprised of 40 and/or 42 residues. Both of them show an affinity to a lipid membrane, but Aβ 42 (a.a. 1-42) is more likely to form amyloid fibrils. 6)This strong tendency of Aβ 42 to aggregate is related to two additional hydrophobic amino acids at its C-terminal end. 7)According to an in vivo study, 8) soluble Aβ oligomers were sequestered from brain interstitial fluid onto brain membranes more rapidly than non-toxic monomers and they were strongly bound to GM1-ganglioside on the cellular membranes. GM1 is likely to form a cluster on a membrane containing sphingomyelin (SM) and cholesterol (Chol). A GM1 cluster has a hydrophobic surface and a negatively charged area due to the condensation of glycans. Many in vitro studies have shown an acceleration of Aβ aggregation on lipid micro-d...

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