Amyloid-β Tetramers and Divalent Cations at the Membrane/Water Interface: Simple Models Support a Functional Role

Abstract

Charge polarization at the membrane interface is a fundamental process in biology. Despite the lower concentration compared to the abundant monovalent ions, the relative abundance of divalent cations (Ca2+, Mg2+, Zn2+, Fe2+, Cu2+) in particular spaces, such as the neuron synapse, raised many questions on the possible effects of free multivalent ions and of the required protection of membranes by the eventual defects caused by the free forms of the cations. In this work, we first applied a recent realistic model of divalent cations to a well-investigated model of a polar lipid bilayer, di-myristoyl phosphatidyl choline (DMPC). The full atomistic model allows a fairly good description of changes in the hydration of charged and polar groups upon the association of cations to lipid atoms. The lipid-bound configurations were analyzed in detail. In parallel, amyloid-β 1–42 (Aβ42) peptides assembled into tetramers were modeled at the surface of the same bilayer. Two of the protein tetramers’ models were loaded with four Cu2+ ions, the latter bound as in DMPC-free Aβ42 oligomers. The two Cu-bound models differ in the binding topology: one with each Cu ion binding each of the monomers in the tetramer; one with pairs of Cu ions linking two monomers into dimers, forming tetramers as dimers of dimers. The models here described provide hints on the possible role of Cu ions in synaptic plasticity and of Aβ42 oligomers in storing the same ions away from lipids. The release of structurally disordered peptides in the synapse can be a mechanism to recover ion homeostasis and lipid membranes from changes in the divalent cation concentration.