Interactions of Aβ25-35 β-barrel-like oligomers with anionic lipid bilayer and resulting membrane leakage: an all-atom molecular dynamics study

J Phys Chem B. 2011 Feb 10;115(5):1165-74. doi: 10.1021/jp107558e. Epub 2010 Dec 30.

Abstract

Aβ25-35, a proteolytic fragment of the Alzheimer amyloid beta (Aβ) peptide, is produced in the brains of Alzheimer's patients and retains the neurotoxicity of its full-length counterpart. The formation of pores/channels in membranes has been reported as one of the mechanisms responsible for Aβ25-35 toxicity. In addition, it has been proposed that pore/channel might be formed by the aggregation of Aβ25-35 in membranes into a β-barrel structure. However, the structure of the β-barrel and its perturbation on the ordering of lipid bilayer at atomic level remain elusive. In this study, we have investigated the interactions of three types of preformed Aβ25-35 β-barrels (labeled as barrels A, B, and C) with negatively charged palmitoyloleoylphosphatidylglycerol (POPG) lipid bilayers using all-atom molecular dynamics (MD) simulations. Each type of Aβ25-35 β-barrel consists of eight β-strands with positively charged side chains of lysine residues oriented toward the interior or exterior of the barrel. Barrels A, B, and C have respectively an out-of-register mixed parallel-antiparallel (taken from our previous study), in-register mixed parallel-antiparallel, and in-register antiparallel β-strand arrangements. Simulations have been performed by employing the initial configurations where the β-barrels are fully or partially inserted into the bilayer. On the basis of nine independent 150 ns MD runs for the full-insertion system, we found that barrels A and C slightly affect the local ordering of lipid bilayer, while barrel B perturbs the local structure of membrane and even causes membrane leakage for water by forming nanometer-sized hydrophilic pore when lysine residues on its inner side. Two 100 ns MD simulations on partial-insertion system show that partial insertion of Aβ25-35 β-barrel in the bilayer results in a tendency to stay inside for barrel B. These results suggest that barrel B with Lys residues on its inner side is the most likely Aβ25-35 pore structure leading to membrane leakage. Our MD simulations provide significant insight into the atomic resolution structure of Aβ25-35 β-sheet-rich pores and the membrane disruption mechanism induced by Aβ25-35 amyloid pores.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / chemistry*
  • Lipid Bilayers / chemistry*
  • Molecular Dynamics Simulation*
  • Peptide Fragments / chemistry*
  • Phosphatidylglycerols / chemistry
  • Protein Structure, Secondary
  • Temperature

Substances

  • Amyloid beta-Peptides
  • Lipid Bilayers
  • Peptide Fragments
  • Phosphatidylglycerols
  • amyloid beta-protein (25-35)
  • 1-palmitoyl-2-oleoylglycero-3-phosphoglycerol