Insights into membrane-bound presenilin 2 from all-atom molecular dynamics simulations

Presenilins 1 and 2 (PS1 or PS2) are main genetic risk factors of familial Alzheimer's disease (AD) that produce the β-amyloid (Aβ) peptides and also have important stand-alone functions related to, e.g. calcium signaling. Most work so far has focused on PS1, but humans carry both PS1 and PS2, and mutations in both cause AD. Here, we develop a computational model of PS2 in the membrane to address the question how pathogenic PS2 mutations affect the membrane-embedded protein. The models are based on cryo-electron microscopy structures of PS1 translated to PS2, augmented with missing residues and a complete all-atom membrane-water system, and equilibrated using three independent 500-ns simulations of molecular dynamics with a structure-balanced force field. We show that the nine-transmembrane channel structure is substantially controlled by major dynamics in the hydrophilic loop bridging TM6 and TM7, which functions as a 'plug' in the PS2 membrane channel. TM2, TM6, TM7 and TM9 flexibility controls the size of this channel. We find that most pathogenic PS2 mutations significantly reduce stability relative to random mutations, using a statistical ANOVA test with all possible mutations in the affected sites as a control. The associated loss of compactness may also impair calcium affinity. Remarkably, similar properties of the open state are known to impair the binding of substrates to γ-secretase, and we thus argue that the two mechanisms could be functionally related.Communicated by Ramaswamy H. Sarma.