Abstract
The amyloid precursor protein (APP), through its amyloidogenic cleavage, generates the membrane-bound C-terminal fragment APP-CTFβ, which accumulates at excitatory presynaptic terminals and contributes to altered synaptic function. To understand the molecular mechanisms driving this effect, we employed both all-atom and coarse-grained molecular dynamics (MD) simulations to model APP-CTFβ in membrane environments representative of the neuronal presynapse. The simulations revealed a stable electrostatic interaction between Arg76 and PIP2 lipid head groups, which tethered the C-terminal helix to the membrane surface. This positioning may regulate access to synaptic vesicle fusion partners.
To investigate longer-timescale and multimeric behavior, we employed coarse-grained MD simulations using the Martini3 force field. APP-CTFβ monomers, dimers, and trimers were simulated in both simplified POPC membranes and more complex presynaptic-like bilayers. These simulations demonstrated that APP-CTFβ spontaneously forms oligomers, and that dimerization and trimerization reduce the Arg76–PIP2 interaction, freeing the C-terminal helix to extend into the cytosol. Additionally, oligomer formation caused local thinning of the membrane bilayer, particularly in the trimeric state, potentially facilitating synaptic vesicle fusion. Together, these computational results support a mechanism by which local concentration and oligomerization of APP-CTFβ enhance synaptic vesicle release by modulating both membrane structure and protein-lipid interactions at the active zone.