cn500277f_si_003.mpg (7.44 MB)
Modulation of Alzheimer’s Aβ Protofilament-Membrane Interactions by Lipid Headgroups
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posted on 2015-03-18, 00:00 authored by Florentina Tofoleanu, Bernard
R. Brooks, Nicolae-Viorel BucheteThe
molecular pathogenesis of Alzheimer’s disease (AD) is complex
and sparsely understood. The relationship between AD’s amyloid
β (Aβ) peptides and neuronal membranes is central to Aβ’s
cytotoxicity and is directly modulated by the composition of the lipid
headgroups. Molecular studies of the insertion of model Aβ40 protofilaments in lipid bilayers revealed strong interactions
that 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. Here, we use all-atom molecular
dynamics and steered molecular dynamics simulations to systematically
compare the effects that POPE and palmytoil-oleoyl-phosphatidylcholine
(POPC) headgroups have on the Aβ–lipid interactions.
We find that Aβ protofilaments exhibit weaker electrostatic
interactions with POPC headgroups and establish significantly shorter-lived
contacts with the POPC bilayer. This illustrates the crucial yet complex
role of electrostatic and hydrogen bonding interactions in modulating
the anchoring and insertion of Aβ peptides into lipid bilayers. Our study reveals the
atomistic details behind the barrier created by the lipid headgroup
region in impeding solution-aggregated fibrillar oligomers to spontaneously
insert into POPC bilayers, in contrast to the POPE case. While the
biological reality is notoriously more complex (e.g., including other
factors such as cholesterol), our results evidence a simple experimentally
and computationally testable case for probing the factors that control
the insertion of Aβ oligomeric aggregates in neuronal cell membranesa
process central to their neurotoxicity.