Membrane interactions of a self-assembling model peptide that mimics the self-association, structure and toxicity of Aβ(1–40)

Abstract

β-amyloid peptide (Aβ) is a primary protein component of senile plaques in Alzheimer’s disease (AD) and plays an important, but not fully understood role in neurotoxicity. Model peptides with the demonstrated ability to mimic the structural and toxicity behavior of Aβ could provide a means to evaluate the contributions to toxicity that are common to self–associating peptides from many disease states. In this work, we have studied the peptide-membrane interactions of a model β-sheet peptide, P11-2 (CH3CO-Gln-Gln-Arg-Phe-Gln-Trp-Gln-Phe-Glu-Gln-Gln-NH2), by fluorescence, infrared spectroscopy, and hydrogen-deuterium exchange. Like Aβ(1-40), the peptide is toxic, and conditions which produce intermediate oligomers show higher toxicity against cells than either monomeric forms or higher aggregates of the peptide. Further, P11-2 also binds to both zwitterionic (POPC) and negatively charged (POPC:POPG) liposomes, acquires a partial β-sheet conformation in presence of lipid, and is protected against deuterium exchange in the presence of lipids. The results show that a simple rationally designed model β-sheet peptide recapitulates many important features of Aβ peptide structure and function, reinforcing the idea that toxicity arises, at least in part, from a common mode of action on membranes that is independent of specific aspects of the amino acid sequence. Further studies of such well-behaved model peptide systems will facilitate the investigation of the general principles that govern the molecular interactions of aggregation-prone disease-associated peptides with cell and/or membrane surfaces.

Self-assembled peptide-based nanostructures: Smart nanomaterials toward targeted drug delivery

“…Membrane interaction of a model β-sheet self-assembled peptide, P11-2 (CH3CO-Gln-Gln-Arg-Phe-Gln-Trp-Gln-Phe-Glu-Gln-Gln-NH2), was studied by Salay et al in order to mimic the toxicity and structural behavior of β-amyloid peptide (Aβ) [88]. In Alzheimer's disease β-amyloid peptide (Aβ) is a main protein component of plaques.…”

Biochemistry of Amyloid -Protein and Amyloid Deposits in Alzheimer Disease

“…in affecting the binding and oligomerization of Ab is being increasingly examined (Kayed et al 2009;Salay et al 2009;Kotarek and Moss 2010;Sureshbabu et al 2010). Smaller (1-2 nm diameter) synthetic Ab oligomers have a greater tendency to bind such charged species than do those of larger (4-5 nm) size (Cizas et al 2010).…”

Dermaseptin 01 as antimicrobial peptide with rich biotechnological potential: study of peptide interaction with membranes containing Leishmania amazonensis lipid‐rich extract and membrane models

“…Due to the high complexity of the biological cell membranes, one usually employs biomimetic model systems to investigate the effects of composition and physical properties of the phospholipid (PL) matrix on the membrane properties. These models include planar lipid bilayers, multilamellar and unilamellar vesicles, lipid microspheres, micelles, and Langmuir monolayers9–13.…”

“…In some cases, even the precise location of the active molecule can be determined. Many biologically active compounds, including protein and peptides, have been studied using Langmuir lipid films as model membranes10–13, 28, 31–37, despite many of them can interact with both leaflets of a biomembrane.…”