Dataset Information

Modulation of Alzheimer's A? protofilament-membrane interactions by lipid headgroups.

ABSTRACT: The molecular pathogenesis of Alzheimer's disease (AD) is complex and sparsely understood. The relationship between AD's amyloid ? (A?) peptides and neuronal membranes is central to A?'s cytotoxicity and is directly modulated by the composition of the lipid headgroups. Molecular studies of the insertion of model A?40 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 A? 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 A?-lipid interactions. We find that A? 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 A? 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 A? oligomeric aggregates in neuronal cell membranes--a process central to their neurotoxicity.

SUBMITTER: Tofoleanu F

PROVIDER: S-EPMC6487634 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Modulation of Alzheimer's Aβ protofilament-membrane interactions by lipid headgroups.

Tofoleanu Florentina F Brooks Bernard R BR Buchete Nicolae-Viorel NV

ACS chemical neuroscience 20150129 3

The 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, electrost ...[more]

PMID: 25581460

Similar Datasets

Project description:Natural or synthetic polycations are used as biocides or as drug/gene carriers. Understanding the interactions between these macromolecules and cell membranes at the molecular level is therefore of great importance for the design of effective polymer biocides or biocompatible polycation-based delivery systems. Until now, details of the processes at the interface between polycations and biological systems have not been fully recognized. In this study, we consider the effect of strong polycations with quaternary ammonium groups on the properties of anionic lipid membranes that we use as a model system for protein-free cell membranes. For this purpose, we employed experimental measurements and atomic-scale molecular dynamics (MD) simulations. MD simulations reveal that the polycations are strongly hydrated in the aqueous phase and do not lose the water shell after adsorption at the bilayer surface. As a result of strong hydration, the polymer chains reside at the phospholipid headgroup and do not penetrate to the acyl chain region. The polycation adsorption involves the formation of anionic lipid-rich domains, and the density of anionic lipids in these domains depends on the length of the polycation chain. We observed the accumulation of anionic lipids only in the leaflet interacting with the polymer, which leads to the formation of compositionally asymmetric domains. Asymmetric adsorption of the polycation on only one leaflet of the anionic membrane strongly affects the membrane properties in the polycation-membrane contact areas: (i) anionic lipid accumulates in the region near the adsorbed polymer, (ii) acyl chain ordering and lipid packing are reduced, which results in a decrease in the thickness of the bilayer, and (iii) polycation-anionic membrane interactions are strongly influenced by the presence and concentration of salt. Our results provide an atomic-scale description of the interactions of polycations with anionic lipid bilayers and are fully supported by the experimental data. The outcomes are important for understanding the correlation of the structure of polycations with their activity on biomembranes.

Dataset Information

Modulation of Alzheimer's A? protofilament-membrane interactions by lipid headgroups.

Publications

Modulation of Alzheimer's Aβ protofilament-membrane interactions by lipid headgroups.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets