MD-simulations of Beta-Amyloid Protein Insertion Efficiency and Kinetics into Neuronal Membrane Mimics

Early interaction events of beta-amyloid (A$\beta )$ peptides with the neuronal membranes play a key role in the pathogenesis of Alzheimer's disease. We have used all-atom MD simulations to study the protein insertion efficiency and kinetics of monomeric A$\beta _{40}$ and A$\beta _{42}$ into phosphatidylcholine lipid bilayers (PC) with and without 40 mole{\%} cholesterol (CHOL) that mimic the cholesterol-enriched and depleted lipid nanodomains of the neuronal plasma membranes. Independent replicates of 200-ns simulations of each protein pre-inserted in the upper lipid layer were generated. In PC bilayers, only 25{\%} of A$\beta _{40}$ and 50{\%} of A$\beta _{42}$ in the replicates showed complete insertion into the lower lipid layer, whereas the percentages increased to 50{\%} and 100{\%}, respectively, in PC/CHOL bilayers, providing evidence that cholesterol improves the protein insertion efficiency into the bilayers. The rate of protein insertion was proportional to the hydrophobic, transmembrane helix length of the inserted peptide and depended on the cholesterol content. We propose that the lysine snorkeling and C-terminus anchoring of A$\beta $ to the PC headgroups at the upper and lower lipid/water interfaces represent the dual-transmembrane stabilization mechanisms of A$\beta $ in the neuronal membrane domains.