Paper Citing NAMD - Abstract
Yu, Xiang; Zheng, Jie
Cholesterol Promotes the Interaction of Alzheimer beta-Amyloid Monomer with Lipid Bilayer
JOURNAL OF MOLECULAR BIOLOGY, 421:561-571, AUG 24 2012
Cholesterol in the plasma membrane plays an important role in the pathogenesis of Alzheimer's disease, but the exact function of cholesterol in the regulation of amyloid-beta (A beta) generation, aggregation, and toxicity remains elusive. To gain insight into the bioactivity of cholesterol, we investigate the effect of cholesterol levels on the interaction of A beta(1-42) monomer with the zwitterionic 1-palmitoyl-2-oleoylphosphatidylcholine (POPC) bilayer containing different mole fractions of cholesterol from chi = 0, 0.2, to 0.4 using all-atom molecular dynamics simulations. Simulation results show that an increased cholesterol level alters the structure, dynamics, and surface chemistry of the lipid bilayer, leading to increased bilayer thickness, hydrophobic chain order, surface hydrophobicity, and decreased lipid mobility. All these effects significantly promote the binding of A beta, to the lipid bilayer. Mechanistically, the adsorption of A beta on the bilayer is a cooperative process. First, charged residues act as anchors to establish the initial binding of A beta to phosphate headgroups of the bilayer driven by electrostatic interactions, which further facilitates hydrophobic residues to reside on the bilayer. Once hydrophobic residues especially from C-terminus are locked on the bilayer, the interactions among charged residues, lipid bilayer, and calcium ions are optimized to provide additional attractive forces to stabilize A beta adsorbed on or inserted into the lipid bilayer. Inclusion of cholesterol makes this binding process more energetically favorable. Upon adsorption on the bilayer, A beta appears to preferentially adopt alpha-helical or unstructured conformation. This work supports that cholesterol acts as a promoter for A beta-membrane interactions, which would facilitate A beta aggregation and membrane insertion. (C) 2011 Elsevier Ltd. All rights reserved.
