title: Structural insight into the mechanism of amyloid precursor protein recognition by β-secretase 1: A molecular dynamics study.
abstract: 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.
authors: Department of Microbiology, University of Calcutta, 35 Ballygunge Circular Road, Kolkata 700 019, India. Electronic address: sandipanchakraborty.13@gmail.com.
authors: Sandipan
authors: S
authors: Chakraborty
authors: Department of Microbiology, University of Calcutta, 35 Ballygunge Circular Road, Kolkata 700 019, India. Electronic address: soumalee@gmail.com.
authors: Soumalee
authors: S
authors: Basu
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry* / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D006801:Humans; D056004:Molecular Dynamics Simulation; D025341:Principal Component Analysis; D011487:Protein Conformation
chemical_list: D016564:Amyloid beta-Protein Precursor; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
keywords: APP; BACE1; Conformational switching; Electrostatic surface complementarity; Essential dynamics; Molecular dynamics simulation