Mechanisms of irreversible aquaporin-10 inhibition by organogold compounds studied by combined biophysical methods and atomistic simulations
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Mechanisms of irreversible aquaporin-10 inhibition by organogold compounds studied by combined biophysical methods and atomistic simulations. / Pimpão, Catarina; Wragg, Darren; Bonsignore, Riccardo; Aikman, Brech; Pedersen, Per Amstrup; Leoni, Stefano; Soveral, Graça; Casini, Angela.
In: Metallomics, Vol. 13, No. 9, mfab053, 2021.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Mechanisms of irreversible aquaporin-10 inhibition by organogold compounds studied by combined biophysical methods and atomistic simulations
AU - Pimpão, Catarina
AU - Wragg, Darren
AU - Bonsignore, Riccardo
AU - Aikman, Brech
AU - Pedersen, Per Amstrup
AU - Leoni, Stefano
AU - Soveral, Graça
AU - Casini, Angela
N1 - Publisher Copyright: © The Author(s) 2021. Published by Oxford University Press.
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - aquaglyceroporin
KW - glycerol transport
KW - gold compounds
KW - irreversible inhibitors
KW - metadynamics
KW - water
U2 - 10.1093/mtomcs/mfab053
DO - 10.1093/mtomcs/mfab053
M3 - Journal article
C2 - 34468767
AN - SCOPUS:85116172061
VL - 13
JO - Metallomics
JF - Metallomics
SN - 1756-5901
IS - 9
M1 - mfab053
ER -
ID: 284085933