Structural insight into the mechanism of amyloid precursor protein recognition by β-secretase 1: A molecular dynamics study

•Free BACE1 exists as a conformational ensemble, visits both open and closed forms.•Concerted movement of flap and other loops leads to open to closed transition.•Cavity closing of BACE1 is a hinge movement between the N- and C-terminal domains.•Binding of APP to the BACE1 is a conformational selection process.•Flap region appropriately orients the APP cut-site towards the catalytic ASP dyad.

β-secretase 1 (BACE1) initiates the proteolysis of amyloid precursor protein (APP) to generate Aβ, aggregation of which has been considered to be the main histopathological feature of Alzheimer's Disease. Here, we have explored the conformational switching of BACE1 during APP recognition using molecular dynamics simulation thereby suggesting the recognition to be a conformational selection process. Free BACE1 is highly flexible and exists as an ensemble of conformations. The β-hairpin flap that covers the active site of BACE1 visits numerous conformations during the simulation. Essential dynamics reveal that concerted movements in several loops including the flap region lead to a conformational switching from open to closed form. During the simulation, free BACE1 visits both the open and closed forms multiple times. Binding of APP to the BACE1 cavity shifts the equilibrium towards a stable complex stabilized by strong electrostatic surface complementarity along with several van der Waals and hydrogen bonding interactions.

Graphical abstractFree BACE1 is highly flexible and exists as an ensemble of conformations. The β-hairpin flap and other loop regions of the active site of BACE1 visit numerous conformations during the simulation. During the simulation time-scale, BACE1 visits both the open and closed form multiple times. Binding of APP to the BACE1 cavity shifts the equilibrium towards a stable complex.Download full-size image