Effects of Salt and Lipids on Conformational Dynamics of the Aβ42 Protein

It is well established that amyloid β-protein (Aβ) self-assembly is involved in triggering of Alzheimer's disease. However, evidence of physiological function of Aβ has only begun to emerge. Details of Aβ-lipid interactions, which may underlie physiological and pathological activities of Aβ, are not well understood. Here, the effects of salt and 1,2-Dimyristoyl-sn-glycero-3-phosphocholine (DMPC) lipids on conformational dynamics of Aβ42 monomer in water are examined by all-atom molecular dynamics (MD). Ten 250-ns long trajectories were acquired in six sets of conditions: 0, 27, and 109 mM of DMPC lipids and pure water or 150 mM salt. We show that salt facilitates long-range tertiary contacts in Aβ42 and more compact conformations. Adding lipids results in lipid-concentration dependent Aβ42 unfolding. At the high lipid concentration, salt enables the N-terminal region of Aβ42 to form long-range tertiary contacts and interact with lipids, resulting in the formation of a parallel β-strand. Stable lipid-protein complexes whereby the protein is adhered to the lipid cluster, rather than embedded into it, are observed. Aβ residing on the cluster surface may be important for facilitating repair of leaks in the blood-brain barrier without penetrating and damaging cellular membranes.