Investigation of flap flexibility of β-secretase using molecular dynamic simulations

Abstract

Flap motif and its dynamics were extensively reported in aspartate proteases, e.g. HIV proteases and plasmepsins. Herein, we report the first account of flap dynamics amongst different conformations of β-secretase using molecular dynamics simulation. Various parameters were proposed and a selected few were picked which could appropriately describe the flap motion. Three systems were studied, namely Free (BACEFree) and two ligand-bound conformations, which belonged to space groups P6122 (BACEBound1) and C2221 (BACEBound2), respectively and four parameters (distance between the flaps tip residue, Thr72 and Ser325, d1; dihedral angle, ϕ (Thr72-Asp32-Asp228-Ser325); TriCα angles, θ1 (Thr72-Asp32-Ser325), and θ2 (Thr72-Asp228-Ser325)) were proposed to understand the change in dynamics of flap domain and the extent of flap opening and closing. Analysis of, θ2, d1, θ1 and ϕ confirmed that the BACEFree adopted semi-open, open and closed conformations with slight twisting during flap opening. However, BACEBound1 (P6122) showed an adaptation to open conformation due to lack of hydrogen bond interaction between the ligand and flap tip residue. A slight flap twisting, ϕ (lateral twisting) was observed for BACEBound1 during flap opening which correlates with the opening of BACEFree. Contradictory to the BACEBound1, the BACEBound2 locked the flap in a closed conformation throughout the simulation due to formation of a stable hydrogen bond interaction between the flap tip residue and ligand. Analyses of all three systems highlight that d1, θ2 and ϕ can be precisely used to describe the extent of flap opening and closing concurrently with snapshots along the molecular dynamics trajectory across several conformations of β-secretase.

Unveiling a novel transient druggable pocket in BACE-1 through molecular simulations: Conformational analysis and binding mode of multisite inhibitors

“…The open conformation of the flap in apo structures of the enzyme [12–14] would allow the access of the substrate and the release of hydrolysis products. In contrast, a closed conformation is found in ligand-bound complexes, even though the degree of opening/closure varies among different X-ray structures [15–17], thus reflecting the structural flexibility of the flap.…”

Flap Dynamics in Aspartic Proteases: A Computational Perspective

“…β ‐hairpin loop (from 67 to 77 residues) covers the binding cleft and is called the flap (Figure ). By a similar mechanism as described above in case of HIV protease and plasmepsin, the access of the inhibitor to the active site is facilitated by the movement of the flap .…”

“…In a recent study, Kumalo et al . provided further analysis of the flap motion of β ‐secretase. They monitored four geometrical parameters (same as Karubiu et al .…”

“…Pictorial representation of parameters used by Kumalo et al . as a reference to understand flap dynamics in BACE .…”

Multidisciplinary approaches for targeting the secretase protein family as a therapeutic route for Alzheimer's disease

“…In a recent study, Kumalo et al provided further analysis of the flap motion of β‐secretase. By monitoring four parameters (distance between the flaps tip residue, Thr72 and Ser325, d1; dihedral angle, ϕ [Thr72‐Asp32‐Asp228‐Ser325]; TriCα angles, θ1 [Thr72‐Asp32‐Ser325], and θ2 [Thr72‐Asp228‐Ser325]), the authors proposed to understand the change in dynamics of the flap domain and the extent of the flap opening and closing in BACE1.…”