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Mechanism and kinetics of Aztreonam hydrolysis catalyzed by class-C β-lactamase : a temperature-accelerated sliced sampling study
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Awasthi, Shalini, Gupta, Shalini, Tripathi, Ravi and Nair, Nisanth N. (2018) Mechanism and kinetics of Aztreonam hydrolysis catalyzed by class-C β-lactamase : a temperature-accelerated sliced sampling study. The Journal of Physical Chemistry B, 122 (15). pp. 4299-4308. doi:10.1021/acs.jpcb.8b01287 ISSN 1520-6106.
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Official URL: http://dx.doi.org/10.1021/acs.jpcb.8b01287
Abstract
Enhanced sampling of large number of collective variables (CVs) is inevitable in molecular dynamics (MD) simulations of complex chemical processes such as enzymatic reactions. Because of the computational overhead of hybrid quantum mechanical/molecular mechanical (QM/MM)-based MD simulations, especially together with density functional theory, predictions of reaction mechanism, and estimation of free-energy barriers have to be carried out within few tens of picoseconds. We show here that the recently developed temperature-accelerated sliced sampling method allows one to sample large number of CVs, thereby enabling us to obtain rapid convergence in free-energy estimates in QM/MM MD simulation of enzymatic reactions. Moreover, the method is shown to be efficient in exploring flat and broad free-energy basins that commonly occur in enzymatic reactions. We demonstrate this by studying deacylation and reverse acylation reactions of aztreonam drug catalyzed by a class-C β lactamase (CBL) bacterial enzyme. Mechanistic details and nature of kinetics of aztreonam hydrolysis by CBL are elaborated here. The results of this study point to characteristics of the aztreonam drug that are responsible for its slow hydrolysis.
Item Type: | Journal Article | ||||||||||||
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Subjects: | Q Science > QD Chemistry Q Science > QP Physiology R Medicine > RM Therapeutics. Pharmacology |
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Divisions: | Faculty of Science, Engineering and Medicine > Engineering > WMG (Formerly the Warwick Manufacturing Group) | ||||||||||||
Library of Congress Subject Headings (LCSH): | Aztreonam -- Research, Molecular dynamics -- Simulation methods, Enzymatic analysis, Density functionals | ||||||||||||
Journal or Publication Title: | The Journal of Physical Chemistry B | ||||||||||||
Publisher: | American Chemical Society | ||||||||||||
ISSN: | 1520-6106 | ||||||||||||
Official Date: | 19 April 2018 | ||||||||||||
Dates: |
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Volume: | 122 | ||||||||||||
Number: | 15 | ||||||||||||
Page Range: | pp. 4299-4308 | ||||||||||||
DOI: | 10.1021/acs.jpcb.8b01287 | ||||||||||||
Status: | Peer Reviewed | ||||||||||||
Publication Status: | Published | ||||||||||||
Reuse Statement (publisher, data, author rights): | “This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Physical Chemistry B, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://pubs.acs.org/page/policy/articlesonrequest/index.html].” | ||||||||||||
Access rights to Published version: | Restricted or Subscription Access | ||||||||||||
Copyright Holders: | American Chemical Society | ||||||||||||
Date of first compliant deposit: | 3 September 2018 | ||||||||||||
Date of first compliant Open Access: | 19 March 2019 | ||||||||||||
RIOXX Funder/Project Grant: |
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