Binding of β-Amyloid (1–42) Peptide to Negatively Charged Phospholipid Membranes in the Liquid-Ordered State: Modeling and Experimental Studies

Abstract

To explore the initial stages of amyloid β peptide (Aβ42) deposition on membranes, we have studied the interaction of Aβ42 in the monomeric form with lipid monolayers and with bilayers in either the liquid-disordered or the liquid-ordered (L(o)) state, containing negatively charged phospholipids. Molecular dynamics (MD) simulations of the system have been performed, as well as experimental measurements. For bilayers in the L(o) state, in the absence of the negatively charged lipids, interaction is weak and it cannot be detected by isothermal calorimetry. However, in the presence of phosphatidic acid, or of cardiolipin, interaction is detected by different methods and in all cases interaction is strongest with lower (2.5-5 mol%) than higher (10-20 mol%) proportions of negatively charged phospholipids. Liquid-disordered bilayers consistently allowed a higher Aβ42 binding than L(o) ones. Thioflavin T assays and infrared spectroscopy confirmed a higher proportion of β-sheet formation under conditions when higher peptide binding was measured. The experimental results were supported by MD simulations. We used 100 ns MD to examine interactions between Aβ42 and three different 512 lipid bilayers consisting of palmitoylsphingomyelin, dimyristoyl phosphatidic acid, and cholesterol in three different proportions. MD pictures are different for the low- and high-charge bilayers, in the former case the peptide is bound through many contact points to the bilayer, whereas for the bilayer containing 20 mol% anionic phospholipid only a small fragment of the peptide appears to be bound. The MD results indicate that the binding and fibril formation on the membrane surface depends on the composition of the bilayer, and is the result of a subtle balance of many inter- and intramolecular interactions between the Aβ42 and membrane.

Specifically designed peptide structures effectively suppressed oxidative reactions in chemical and cellular systems

“…A vast number of human diseases are associated with protein misfolding and extracellular formation of highly organized aggregates with fibrillar morphology (Ahyayauch et al, 2012). Evidence shows that short peptides are involved in regulating the proper folding of proteins, which implicates the possible role of peptides in prevention of amyloid fibrilogenesis.…”

“…Antioxidant peptides, aside from their nutritional benefits, can suppress the oxidation reactions through various mechanisms including inactivation of reactive oxygen species, free radicals scavenging, chelation of pro-oxidative transition metals and promoting the enzymatic elimination of specific oxidants (Bamdad, Wu, & Chen, 2011). In a related area of research, free radical reactions are shown to be the critical step in amyloid fibril formation (Ahyayauch et al, 2012). Normal cell functions are disturbed by the aberrant aggregation of proteins leading to highly ordered protein assemblies such as amyloid fibrils (Gazit, 2005).…”

“…According to the recent studies, hydrophobic interactions and hydrogen bonding play critical roles in forming a highly ordered fibril structure (Ahyayauch et al, 2012). Exposed hydrophobic zones of the unfolded protein chains promote their association into a network and hydrogen bonds stabilize their primary association to form a nucleus (Ahyayauch et al, 2012). This could clearly explain the positive contribution of the Gln and Tyr residues to inhibit aggregation by hydrogen bonding and hydrophobic interactions, respectively.…”

“…It was also shown that the charged opioid peptides had lower capacity to inhibit fibril formation compared to more hydrophobic peptides (Artemova et al, 2010). According to the recent studies, hydrophobic interactions and hydrogen bonding play critical roles in forming a highly ordered fibril structure (Ahyayauch et al, 2012). Exposed hydrophobic zones of the unfolded protein chains promote their association into a network and hydrogen bonds stabilize their primary association to form a nucleus (Ahyayauch et al, 2012).…”

The Interaction of Bio-Molecules with Lipid Membranes Studied by X-ray Diffraction

“…As such, this short transmembrane segment is often used in studies of the protein interactions and partitioning in the membrane [47,48]. While A peptides are frequently reported in an extracellular location, A 1-40 and A 1-42 molecules were found to strongly interact with negatively charged lipids and to bind to anionic, negatively charged membranes [49][50][51][52][53][54][55], orienting parallel to the membrane surface. Through X-ray and neutron diffraction, Mason et al [56] and Dante, Hauß and Dencher [47] observed an embedded state for the A 25-35 segment and the full-length A 1-42 peptide in anionic lipid membranes [57].…”