Mechanisms of irreversible aquaporin-10 inhibition by organogold compounds studied by combined biophysical methods and atomistic simulations

Pimpao, Catarina, Wragg, Darren, Bonsignore, Riccardo, Aikman, Brech, Pedersen, Per Amstrup, Leoni, Stefano ORCID: https://orcid.org/0000-0003-4078-1000, Soveral, Graça and Casini, Angela ORCID: https://orcid.org/0000-0003-1599-9542 2021. Mechanisms of irreversible aquaporin-10 inhibition by organogold compounds studied by combined biophysical methods and atomistic simulations. Metallomics 13 (9) , mfab053. 10.1093/mtomcs/mfab053

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Abstract

The inhibition of glycerol permeation via human aquaporin-10 (hAQP10) by organometallic gold complexes has been studied by stopped-flow fluorescence spectroscopy, and its mechanism has been described using molecular modelling and atomistic simulations. The most effective hAQP10 inhibitors are cyclometalated Au(III) C^N compounds known to efficiently react with cysteine residues leading to the formation of irreversible C–S bonds. Functional assays also demonstrate the irreversibility of the binding to hAQP10 by the organometallic complexes. The obtained computational results by metadynamics show that the local arylation of Cys209 in hAQP10 by one of the gold inhibitors is mapped into a global change of the overall free energy of glycerol translocation across the channel. Our study further pinpoints the need to understand the mechanism of glycerol and small molecule permeation as a combination of local structural motifs and global pore conformational changes, which are taking place on the scale of the translocation process and whose study, therefore, require sophisticated molecular dynamics strategies.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Advanced Research Computing @ Cardiff (ARCCA) Chemistry
Publisher:	Oxford University Press
ISSN:	1756-591X
Date of First Compliant Deposit:	8 November 2021
Date of Acceptance:	18 August 2021
Last Modified:	08 Nov 2024 21:30
URI:	https://orca.cardiff.ac.uk/id/eprint/145367

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