REPLICA-EXCHANGE MOLECULAR DYNAMICS SIMULATIONS OF AMYLOID PRECURSOR PROTEIN DIMER IN MEMBRANE

摘要

Aggregation of amyloid β peptide (Aβ) in the brain is the primary element in the pathogenesis of Alzheimer's disease. Aβ is derived from amyloid precursor protein (APP) in the membrane due to the cleavages by β- and γ-secretases. Here, we predict the transmembrane structures of the wild-type and mutant APP in the biological membrane by replica-exchange molecular dynamics simulations. The simulations illustrate large conformational differences between the wild type and mutant APP fragments in the membrane. Dimerization of the wild type occurs due to the Cα-H...O hydrogen bonds at the Gly-XXX-Gly motifs between two APP fragments, whereas the mutant dimer is stabilized by the interactions between hydrophobic side chains. We also observe the downward shift of y-cleavage site in the mutant APP, which may cause the prohibition of Aβ production.