Abstract
AbstractWe have used a systems biology approach to address the hitherto insoluble problem of the quantitative analysis of non-equilibrium binding of aqueous metal ions by competitive ligands in heterogeneous media. To-date, the relative proportions of different metal complexes in aqueous media have only been modelled at chemical equilibrium and there are no quantitative analyses of the approach to equilibrium1. While these models have improved our understanding of how metals are used in biological systems they cannot account for the influence of kinetic factors in metal binding, transport and fate2. Here we have modelled the binding of aluminium in blood serum by the iron transport protein transferrin (Tf) as it is widely accepted that the biological fate of this non-essential metal is not adequately described by experiments, in vitro and in silico, which have consistently demonstrated that at equilibrium 90% of serum Al(III) is bound by Tf3-5. We have coined this paradox 'the blood-aluminium problem'6 and herein applied a systems biology approach which utilised well-found assumptions to pare away the complexities of the problem such that it was defined by a comparatively simple set of computational rules and, importantly, its solution assumed significant predictive capabilities. Here we show that our novel computational model successfully described the binding of Al(III) by Tf both at equilibrium and as equilibrium for AlTf was approached. The model provided an explanation of why the distribution of Al(III) in the body cannot be adequately described by its binding and transport by Tf and it highlighted the significance of kinetic in addition to thermodynamic constraints in defining the fate of metal ions in biological systems. This is the first model of non-equilibrium metal binding in a biological system and it should prove to be a valuable predictive tool in furthering our understanding of the bioinorganic chemistry of metals.
Highlights
We have used a systems biology approach to address the hitherto insoluble problem of the quantitative analysis of non-equilibrium binding of aqueous metal ions by competitive ligands in heterogeneous media
While the results of these studies are in agreement in having demonstrated that at chemical equlibrium ca 90% of serum Al(III) was complexed by Tf there was a consensus of opinion which conceded that the equilibrium position was unlikely to be effective in vivo[3,4,5,6,7,8,9]
We called this paradox the blood-aluminium problem[6] and because we believed that its solution would not be accessible by conventional wet chemical methods it became the focus of a computational approach, which is described in full elsewhere[10], and applied for the first time
Summary
The exceptional conditions were when the ratio of Al:Tf = 1.0 (2000 Al) where in both systems equilibrium was approached from under-saturation and it was predicted that only ca 75% of Al(III) would be AlTf. As a predictive model of a biological system the data obtained at chemical equilibrium have accurately modelled what is already known, that ca 90% of Al(III) will be bound by Tf, and predicted an unknown, that the proportion of Al(III) bound by Tf would be lower at higher concentrations of Al(III).
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