The C55 Peptide Portion of the Amyloid Precurosr Protein can Form Stable Dimers

Abstract

Alzheimer's disease (AD) is a neurodegenerative disease of profound cost in terms of economic impact and human suffering that is becoming prevalent as life expectancy in the world's population rises. An important step in the pathology of Alzheimer's disease is the production of toxic amyloid β peptides (Aβ) by the processive cleavage of the amyloid precursor protein (APP). APP is cleaved by β-secretase producing C99 peptide which is processivity cleaved by γ-secretase to produce Aβ. There is no consensus on the effect APP dimerization has on γ-secretase cleavage and Aβ production, as studies have shown that APP dimers inhibits cleavage and others show APP dimers promote cleavage by γ-secretase. To further illuminate the effect of APP dimerization on its cleavage by γ-secretase, the structure of the APP dimer is needed. Using coarse grained enhanced sampling by the molecular dynamics engine, Upside (Jumper et. al. PLOS Computational Biology 2018), we created a large ensemble structure of C55 (the intermembrane and Aβ part of C99) dimers. After using principle component analysis (PCA) and k-means clustering we chose 10 starting conformations of the C55 dimer, which were then equilibrated for 100 nanoseconds in an explicit all-atom POPC membrane. PCA of these trajectories showed 7 possible stable dimer conformations. Dimers were mainly stabilized by interactions of hydrophobic residues and residues in the GxxxG zipper motif. The G37/38 helix kink and curvature of the helices observed experimentally in C99, were not observed in our conformations. initial binding free energy calculations for these dimers show strong interactions which are indicative of the viability, and stability, for these structures. These conformations can be used to assess the effect APP dimerization has on its cleavage mechanism of γ-secretase and the production of Aβ.