Paper Citing NAMD - Abstract
Tofoleanu, Florentina; Brooks, Bernard R.; Buchete, Nicolae-Viorel
Modulation of Alzheimer's A beta Protofilament-Membrane Interactions by Lipid Headgroups
ACS CHEMICAL NEUROSCIENCE, 6:446-455, MAR 2015
The molecular pathogenesis of Alzheimer's POPE disease (AD) is complex and sparsely understood. The relationship between AD's amyloid beta (A beta) peptides and neuronal membranes is central to A beta's cytotoxicity and is directly modulated by the composition of the lipid headgroups. Molecular studies of the insertion of model A beta(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 beta 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 beta-lipid interactions. We find that A beta 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 beta 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 beta oligomeric aggregates in neuronal cell membranes-a process central to their neurotoxicity.
