科研之友
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摘要
Because the amyloid beta-peptide (A beta) functions as approximately half of the transmembrane domain of the amyloid precursor protein and interaction of A beta with membranes is proposed to result in neurotoxicity, the association of A beta with membranes likely is important in the etiology of Alzheimer's disease. Atomic details of the interaction of A beta 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 beta-peptide (A beta(40)) embedded in a dipalmitoylphosphatidylcholine (DPPC) bilayer. The present study examines the effects of insertion depth, protonation state of key residues, and ionic strength on A beta(40) in a DPPC bilayer. In all cases, a portion of the peptide remained embedded in the bilayer. In the case of deeper insertion depth, A beta(40) 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 beta-strand was noted in one case. Our results compare well with a variety of experimental and computational findings. From this study, we conclude that A beta 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.
- 出版日期2008-2-1
