A comparative molecular dynamics analysis of the amyloid beta-peptide in a lipid bilayer

Because the amyloid β-peptide (Aβ) functions as approximately half of the transmembrane domain of the amyloid precursor protein and interaction of Aβ with membranes is proposed to result in neurotoxicity, the association of Aβ with membranes likely is important in the etiology of Alzheimer’s disease. Atomic details of the interaction of Aβ with membranes are not accessible with most experimental techniques, but computational methods can provide this information. Here, we present the results of ten 100-ns molecular dynamics (MD) simulations of the 40-residue amyloid β-peptide (Aβ₄₀) embedded in a dipalmitoylphosphatidylcholine (DPPC) bilayer. The present study examines the effects of insertion depth, protonation state of key residues, and ionic strength on Aβ₄₀ in a DPPC bilayer. In all cases, a portion of the peptide remained embedded in the bilayer. In the case of deeper insertion depth, Aβ₄₀ adopted a near-transmembrane orientation, drawing water molecules into the bilayer to associate with its charged amino acids. In the case of shallower insertion, the most widely-accepted construct, the peptide associated strongly with the membrane-water interface and the phosphatidylcholine headgroups of the bilayer. In most cases, significant disordering of the extracellular segment of the peptide was observed, and the brief appearance of a β-strand was noted in one case. Our results compare well with a variety of experimental and computational findings. From this study, we conclude that Aβ associated with membranes is dynamic and capable of adopting a number of conformations, each of which may have significance in understanding the progression of Alzheimer’s disease.