The interactions of toxic heavy metals with glutathione (GSH), important in view of preserving functionality and high redox regulating capacity of GSH/GSSG system in living organisms, have been studied using representative heavy metal ions, Hg(II). We have found that the modification of Au with a self-assembled glutathione (Au-SG) film creates a framework of confined-space microenvironment with ion-channels for enhanced Hg2+-GSH interactions and rich charge transfer reactivity. The reduction of Hg(II) on a Au-SG piezoelectrode has been investigated in two regimes of ion-channel permeation of the modifying film. At higher Hg(II) concentrations ([Hg(II)] > 1 mM), the ion-channels in Au-SG are open allowing for a free access to Au surface at the bottom of Au-SG channels. The maximum surface coverage determined from the upd-Hg mass: 0(upd-Hg) = 0.31. The chelation of Hg2+ to carboxylate moieties at the outer film/solution boundary and place exchange reactivity of Hg/Au atoms at the sulfur root of adsorbed GSH have been further investigated at lower Hg(II) concentrations to limit the amount of deposited mercury. Ab initio quantum mechanical calculations of electronic properties of interface structures have enabled us to determine geometry of the GSH-Hg2+ chelate which appears to mimic that of GSH-Ca2+ with less than 1% difference in coordination bond lengths. The implications of this finding for studies of environmental effects on susceptibility to degenerative diseases and cancer should be of great significance. (C) 2008 Elsevier B.V. All rights reserved.