Competition between abiogenic Al3+ and native Mg2+, Fe2+ and Zn2+ ions in protein binding sites: implications for aluminum toxicity.

Abstract

Abiogenic aluminum has been implicated in some health disorders in humans. Protein binding sites containing essential metals (mostly magnesium) have been detected as targets for the "alien" Al3+. However, the acute toxicity of aluminum is very low. Although a substantial body of information has been accumulated on the biochemistry of aluminum, the underlying mechanisms of its toxicity are still not fully understood. Several outstanding questions remain unanswered: (1) Why is the toxicity of aluminum, unlike that of other "alien" metal cations, relatively low? (2) Apart from Mg2+ active centers in proteins, how vulnerable are other essential metal binding sites to Al3+ attack? (3) Generally, what factors do govern the competition between 'alien" Al3+ and cognate divalent metal cations in metalloproteins under physiologically relevant conditions? Here, we endeavor to answer these questions by studying the thermodynamic outcome of the competition between Al3+ and a series of biogenic metal cations, such as Mg2+, Fe2+ and Zn2+, in model protein binding sites of various structures, compositions, solvent exposure and charge states. Density functional theory calculations were employed in combination with polarizable continuum model computations. For the first time, the presence of different Al3+ soluble species at physiological pH was properly modeled in accordance with experimental observations. The results suggest that a combination of concentration and physicochemical factors renders the Al3+ → M2+ (M = Mg, Fe, Zn) substitution and subsequent metalloenzyme inhibition a low-occurrence event at ambient pH: the more active aluminum species, [Al(H2O)6]3+, presents in very minute quantities at physiological conditions, while the more abundant soluble aluminum hydrate, {[Al(OH-)4](H2O)2}-, appears to be thermodynamically incapable of substituting for the native cation.