Computational Insights into Substrate and Site Specificities, Catalytic Mechanism, and Protonation States of the Catalytic Asp Dyad of β-Secretase
Joint Authors
Barman, Arghya
Prabhakar, Rajeev
Source
Issue
Vol. 2014, Issue 2014 (31 Dec. 2014), pp.1-11, 11 p.
Publisher
Hindawi Publishing Corporation
Publication Date
2014-09-18
Country of Publication
Egypt
No. of Pages
11
Main Subjects
Abstract EN
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.
American Psychological Association (APA)
Barman, Arghya& Prabhakar, Rajeev. 2014. Computational Insights into Substrate and Site Specificities, Catalytic Mechanism, and Protonation States of the Catalytic Asp Dyad of β-Secretase. Scientifica،Vol. 2014, no. 2014, pp.1-11.
https://search.emarefa.net/detail/BIM-1047577
Modern Language Association (MLA)
Barman, Arghya& Prabhakar, Rajeev. Computational Insights into Substrate and Site Specificities, Catalytic Mechanism, and Protonation States of the Catalytic Asp Dyad of β-Secretase. Scientifica No. 2014 (2014), pp.1-11.
https://search.emarefa.net/detail/BIM-1047577
American Medical Association (AMA)
Barman, Arghya& Prabhakar, Rajeev. Computational Insights into Substrate and Site Specificities, Catalytic Mechanism, and Protonation States of the Catalytic Asp Dyad of β-Secretase. Scientifica. 2014. Vol. 2014, no. 2014, pp.1-11.
https://search.emarefa.net/detail/BIM-1047577
Data Type
Journal Articles
Language
English
Notes
Includes bibliographical references
Record ID
BIM-1047577