The Effect of Amyloid Precursor Protein Dimerization on its Conformation and Cleavage

Abstract

Alzheimer's disease (AD) is an important, increasingly prevalent neurological disorder. Aggregation of Amyloid β (Aβ) is important in etiology of AD. Aβ arises from a specific cut of the Amyloid precursor protein (APP). The C99 peptide part of APP is the intermediary that contains the toxic Aβ1-40 and Aβ1-42 peptides (among other products). A potentially significant feature of C99 is its dimerization behavior that may affect its recognition by the γ-secretase enzyme for cleavage. To understand the mechanisms and effects of dimerization, we simulate the C55 part of C99 peptide (the intermembrane part) at monomeric and dimeric levels using POPC and DMPC lipids. To accelerate the membrane contribution to the conformational changes of C55 without the loss of atomistic detail, we also used the novel high mobility mimetic membrane (HMMM) models of POPC and DMPC. Our large-scale molecular dynamics simulations showed that at the monomeric level the structure displayed dependence on the membrane lipid composition. While the transmembrane helix remained stable, the G37/38 kink observed experimentally did not manifest under different lipid compositions. The extracellular part (residues 1-23) develops β-conformation and the juxta-membrane helix disappeared rather quickly. At the dimeric level, we built four conformations: we clustered our monomer simulations and chose the representatives of the largest clusters as the basis for two initial dimer configurations. For the other two we used structures from Sanders' experimentally determined C99 structure (PDB: 2LP1). We observed that when the N-terminal residues (50-55) of the monomers are in close proximity, the dimer stabilizes. Similarly, interaction of extramembrane residues (1-23) help stabilize the dimer, especially with the presence of β-strands in this region. To better explore the possible conformations of C55-dimers, we are supplementing these observations with enhanced sampling methods.