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BioMed Research International
Volume 2013 (2013), Article ID 170586, 14 pages
http://dx.doi.org/10.1155/2013/170586
Research Article

Computational Analysis of the Soluble Form of the Intracellular Chloride Ion Channel Protein CLIC1

1School of Medical and Molecular Biosciences, University of Technology Sydney, P.O. Box 123, Broadway, NSW 2007, Australia
2School of Physics, University of New South Wales, Sydney, NSW 2052, Australia
3St Vincent’s Centre for Applied Medical Research, St Vincent’s Hospital, Darlinghurst, NSW 2010, Australia

Received 10 April 2013; Revised 26 June 2013; Accepted 27 June 2013

Academic Editor: Serdar Kuyucak

Copyright © 2013 Peter M. Jones et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

The chloride intracellular channel (CLIC) family of proteins has the remarkable property of maintaining both a soluble form and an integral membrane form acting as an ion channel. The soluble form is structurally related to the glutathione-S-transferase family, and CLIC can covalently bind glutathione via an active site cysteine. We report approximately 0.6  s of molecular dynamics simulations, encompassing the three possible ligand-bound states of CLIC1, using the structure of GSH-bound human CLIC1. Noncovalently bound GSH was rapidly released from the protein, whereas the covalently ligand-bound protein remained close to the starting structure over 0.25  s of simulation. In the unliganded state, conformational changes in the vicinity of the glutathione-binding site resulted in reduced reactivity of the active site thiol. Elastic network analysis indicated that the changes in the unliganded state are intrinsic to the protein architecture and likely represent functional transitions. Overall, our results are consistent with a model of CLIC function in which covalent binding of glutathione does not occur spontaneously but requires interaction with another protein to stabilise the GSH binding site and/or transfer of the ligand. The results do not indicate how CLIC1 undergoes a radical conformational change to form a transmembrane chloride channel but further elucidate the mechanism by which CLICs are redox controlled.