UZH-Logo

Maintenance Infos

Dynamics in the active site of β-Secretase: a network analysis of atomistic simulations


Mishra, S; Caflisch, A (2011). Dynamics in the active site of β-Secretase: a network analysis of atomistic simulations. Biochemistry, 50(43):9328-9339.

Abstract

The aspartic protease β-secretase (BACE) catalyzes the hydrolysis of the amyloid precursor protein (APP) which leads to amyloid-β aggregation and, ultimately, the perilous Alzheimer's disease. The conformational dynamics and free energy surfaces of BACE at three steps of the catalytic cycle are studied here by explicit solvent molecular dynamics simulations (multiple runs for a total of 2.2 μs). The overall plasticity of BACE is essentially identical for the three states of the substrate: the octapeptide reactant, gem-diol intermediate, and cleavage products. In contrast, the network of hydrogen bonds in the active site is more stable in the complex of BACE with the gem-diol intermediate than the other two states of the substrate. The spontaneous release of the C-terminal (P1'-P4') fragment of the product follows a single-exponential time dependence with a time constant of 50 ns and does not require the opening of the flap. The fast dissociation of the C-terminal fragment is consistent with the transmembrane location and orientation of APP and its further processing by γ-secretase. On the other hand, the N-terminal (P4-P1) fragment of the product does not exit the BACE active site within the simulation time scale of 80 ns. A unified network analysis of the complexes of BACE with the three states of the substrate provides an estimation of the activation free energy associated with the structural rearrangements that involve only noncovalent interactions. The estimated rearrangement barriers are not negligible (up to 3 kcal/mol) but are significantly smaller than the barrier of the peptide bond hydrolysis reaction.

The aspartic protease β-secretase (BACE) catalyzes the hydrolysis of the amyloid precursor protein (APP) which leads to amyloid-β aggregation and, ultimately, the perilous Alzheimer's disease. The conformational dynamics and free energy surfaces of BACE at three steps of the catalytic cycle are studied here by explicit solvent molecular dynamics simulations (multiple runs for a total of 2.2 μs). The overall plasticity of BACE is essentially identical for the three states of the substrate: the octapeptide reactant, gem-diol intermediate, and cleavage products. In contrast, the network of hydrogen bonds in the active site is more stable in the complex of BACE with the gem-diol intermediate than the other two states of the substrate. The spontaneous release of the C-terminal (P1'-P4') fragment of the product follows a single-exponential time dependence with a time constant of 50 ns and does not require the opening of the flap. The fast dissociation of the C-terminal fragment is consistent with the transmembrane location and orientation of APP and its further processing by γ-secretase. On the other hand, the N-terminal (P4-P1) fragment of the product does not exit the BACE active site within the simulation time scale of 80 ns. A unified network analysis of the complexes of BACE with the three states of the substrate provides an estimation of the activation free energy associated with the structural rearrangements that involve only noncovalent interactions. The estimated rearrangement barriers are not negligible (up to 3 kcal/mol) but are significantly smaller than the barrier of the peptide bond hydrolysis reaction.

Citations

13 citations in Web of Science®
12 citations in Scopus®
Google Scholar™

Altmetrics

Downloads

2 downloads since deposited on 04 Nov 2011
0 downloads since 12 months
Detailed statistics

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Department of Biochemistry
07 Faculty of Science > Department of Biochemistry
Dewey Decimal Classification:570 Life sciences; biology
Date:2011
Deposited On:04 Nov 2011 07:19
Last Modified:05 Apr 2016 15:04
Publisher:American Chemical Society
ISSN:0006-2960
Publisher DOI:10.1021/bi2011948
PubMed ID:21942621
Permanent URL: http://doi.org/10.5167/uzh-50659

Download

[img]
Content: Published Version
Filetype: PDF - Registered users only
Size: 5MB
View at publisher

TrendTerms

TrendTerms displays relevant terms of the abstract of this publication and related documents on a map. The terms and their relations were extracted from ZORA using word statistics. Their timelines are taken from ZORA as well. The bubble size of a term is proportional to the number of documents where the term occurs. Red, orange, yellow and green colors are used for terms that occur in the current document; red indicates high interlinkedness of a term with other terms, orange, yellow and green decreasing interlinkedness. Blue is used for terms that have a relation with the terms in this document, but occur in other documents.
You can navigate and zoom the map. Mouse-hovering a term displays its timeline, clicking it yields the associated documents.

Author Collaborations