Transmembrane structures of amyloid precursor protein dimer predicted by replica-exchange molecular dynamics simulations.

Abeta peptide is an essential protein in the pathogenesis of Alzheimer's disease and is derived from amyloid precursor protein (APP) in the membrane by beta- and gamma-secretase cleavage. An experimental study has shown that a pairwise replacement of Gly with Leu in APP enhances homodimerization but leads to a drastic reduction of Abeta secretion. To resolve this apparent discrepancy, we predicted the wild-type (WT) and mutant APP dimer conformations by replica-exchange molecular dynamics simulations using the implicit membrane model IMM1. The simulations illustrate large conformational differences between the WT and mutant APP fragments in the membrane. Dimerization of the WT is due to two C(alpha)-H...O hydrogen bonds between two APP fragments, whereas dimerization of the mutant is due to hydrophobic interactions. In the mutant, each APP fragment is more tilted, and the gamma-cleavage site is shifted toward the center of the membrane. This position produces a mismatch between the active site of gamma-secretase and the gamma-cleavage site of APP that might prohibit Abeta production.