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Review
. 2014:2014:598728.
doi: 10.1155/2014/598728. Epub 2014 Sep 18.

Computational Insights into Substrate and Site Specificities, Catalytic Mechanism, and Protonation States of the Catalytic Asp Dyad of β -Secretase

Arghya Barman  1 , Rajeev Prabhakar  1
Affiliations
Review

Computational Insights into Substrate and Site Specificities, Catalytic Mechanism, and Protonation States of the Catalytic Asp Dyad of β -Secretase

Arghya Barman et al. Scientifica (Cairo). 2014.

Abstract

In this review, information regarding substrate and site specificities, catalytic mechanism, and protonation states of the catalytic Asp dyad of β-secretase (BACE1) derived from computational studies has been discussed. BACE1 catalyzes the rate-limiting step in the generation of Alzheimer amyloid beta peptide through the proteolytic cleavage of the amyloid precursor protein. Due to its biological functioning, this enzyme has been considered as one of the most important targets for finding the cure for Alzheimer's disease. Molecular dynamics (MD) simulations suggested that structural differences in the key regions (inserts A, D, and F and the 10s loop) of the enzyme are responsible for the observed difference in its activities towards the WT- and SW-substrates. The modifications in the flap, third strand, and insert F regions were found to be involved in the alteration in the site specificity of the glycosylphosphatidylinositol bound form of BACE1. Our QM and QM/MM calculations suggested that BACE1 hydrolyzed the SW-substrate more efficiently than the WT-substrate and that cleavage of the peptide bond occurred in the rate-determining step. The results from molecular docking studies showed that the information concerning a single protonation state of the Asp dyad is not enough to run an in silico screening campaign.

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Figures

Figure 1
Figure 1
Critical regions of BACE1 that participate in the substrate recognition, catalytic Asp dyad, conserved waters (WAT1 and WAT2), and orientation of Tyr71 in open and closed conformation of the flap.
Figure 2
Figure 2
(a) Time evolution of the topological distance between the Cα(Thr72) of flap tip and Cβ(Asp32) of catalytic dyad (violet: BACE1-compound 11, blue: BACE1-SW substrate, red: BACE1-WT substrate, and green: Apo BACE1). (b) Number of hydrogen bonds formed between the substrates and BACE1 (blue: BACE1-SW substrate, red: BACE1-WT substrate). (c) Interaction of the substrate Glu with the Arg307 of BACE1.
Figure 3
Figure 3
General acid-base mechanism utilized for peptide hydrolysis.
Figure 4
Figure 4
Computed barriers for the WT- and SW-substrate using pruned models (with the DFT method) and entire protein (with the ONIOM (QM/MM) method).
Figure 5
Figure 5
Possible protonation states of the two catalytic Asp residues.
Figure 6
Figure 6
Most favorable binding modes of the ligands L1–L8 ((a) to (h), resp.) obtained from the docking procedure.
See this image and copyright information in PMC

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