Molecular interactions between Alzheimer's disease amyloid β (Aβ) peptides and neuronal membranes are directly modulated by the composition of the adjacent lipid headgroups. Our previous molecular studies of the insertion of model Aβ40 protofilaments in lipid bilayers revealed strong interactions that can affect the structural integrity of both the membranes and the ordered amyloid aggregates. In particular, electrostatics plays a crucial role in the interaction between Aβ protofilaments and palmytoil-oleoyl-phosphatidylethanolamine (POPE) lipids, a common component of neuronal plasma membranes. We used all-atom molecular dynamics and steered molecular dynamics simulations to compare systematically the effects of different lipid types in the Aβ-lipid membrane interactions. Our results illustrate the crucial yet complex role of the initial electrostatic interactions in controlling the anchoring and insertion of Aβ in lipid bilayers, and reveals the atomistic details behind the barrier created by the lipid headgroup region. While the biological reality is notoriously more complex (e.g., including other factors such as cholesterol), our study evidences a simple experimentally testable case for probing the factors that control the insertion of Aβ protofilaments in neuronal cell membranes.  These findings unveil detailed molecular mechanisms of Aβ-membrane interactions, and suggest a polymorphic structural character of amyloid ion channels embedded in lipid bilayers.<br/>

Modulation of molecular interactions of Alzheimer's Aβ peptide fibrils and oligomers with lipid membranes

249th National Meeting (2015)

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