A computational model to unravel the function of amyloid-β peptide in contact with a phospholipid membrane

The normal synapse activity involves the release of copper and other divalent cations in the synaptic region. These ions have a strong impact on the membrane properties, especially when the membrane has charged groups, like it is the case of synapse. In this work we use an atomistic computational model of dimyristoyl-phosphatidylcholine (DMPC) membrane bilayer. We perturb this model with a simple model of divalent cation (Mg2+), and with a single amyloid-β (Aβ) peptide of 42 residues, both with and without a single Cu2+ ion bound to the N-terminus. In agreement with experimental results reported in the literature, the model confirms that divalent cations locally destabilize the DMPC membrane bilayer, and, for the first time, that the monomeric form of Aβ helps in avoiding the interactions between divalent cations and DMPC, preventing significant effects on the DMPC bilayer properties. These results are discussed in the frame of a protective role of diluted Aβ peptide floating in the synaptic region.Author summaryWe modelled the behavior of a Mg2+ divalent cation, with the size of Zn2+ and Cu2+, in contact with a phosphatidyl lipid bilayer. We also modelled the monomeric amyloid-β peptide 1-42, both free and Cu-loaded, the latter mimicking the final step of the binding between the peptide and the divalent cation. On the basis of the simulation results, we propose that the peptide hinders the strong interactions between the divalent cation and the membrane.

Molecular dynamics investigation of myelin basic protein stability on lipid membranes

Simulation of proteins and membranes composed of synthetic lipids on computer clusters provides molecular information that complements experimental data. This paper describes molecular dynamics (MD) approaches to study the properties of biological membranes and proteins using the freely available GROMACS package on the C-terminal α-helical peptide of myelin basic protein (MBP). We simulated a mixed membrane – consisting of 2-dimyristoyl-sn-glycero-3-phosphocholine/1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPC/DMPE), and a pure DMPC membrane, composed of 188 and 248 lipids, respectively – for 200 ns at 309K. The DMPC membrane was approximately three times more fluid compared to the DMPC/DMPE system, with the diffusion coefficients (D) being 0.0207x10-5 cm2/s and 0.0068x10-5 cm2/s, respectively. In addition, we simulated the 14-residue peptide representing the C-terminal α-helical region of murine MBP, with sequence NH2-A141YDAQGTLSKIFKL154-COOH, in both membrane systems for 200 ns. The negatively-charged N-terminal end of the peptide penetrated further into the DMPC bilayer than into the mixed DMPC/DMPE bilayer. Reduced peptide accessibility to a formal positive charge of the DMPC amine ‘N’ atom surrounded by methyl and methylene groups may be the cause [1]. The peptide lost its α-helical structure in DMPC/DMPE but not in the DMPC bilayer. These findings show that membrane composition affects MBP’s interaction with it, a phenomenon that provides insights into myelin structure – and that may eventually be relevant to understanding the pathogenesis of multiple sclerosis (MS).