Lanthanides as Calcium Mimetic Species in Calcium-Signaling/Buffering Proteins: The Effect of Lanthanide Type on the Ca(2+)/Ln(3+) Competition

Lanthanides, the 14 4f-block elements plus Lanthanum, have been extensively used to study the structure and biochemical properties of metalloproteins. The characteristics of lanthanides within the lanthanide series are similar, but not identical. The present research offers a systematic investigation of the ability of the entire Ln(3+) series to substitute for Ca(2+) in biological systems. A well-calibrated DFT/PCM protocol is employed in studying the factors that control the metal selectivity in biological systems by modeling typical calcium signaling/buffering binding sites and elucidating the thermodynamic outcome of the competition between the “alien” La(3+)/Ln(3+) and “native” Ca(2+), and La(3+) − Ln(3+) within the lanthanide series. The calculations performed reveal that the major determinant of the Ca(2+)/Ln(3+) selectivity in calcium proteins is the net charge of the calcium binding pocket; the more negative the charge, the higher the competitiveness of the trivalent Ln(3+) with respect to its Ca(2+) contender. Solvent exposure of the binding site also influences the process; buried active centers with net charge of −4 or −3 are characterized by higher Ln(3+) over Ca(2+) selectivity, whereas it is the opposite for sites with overall charge of −1. Within the series, the competition between La(3+) and its fellow lanthanides is determined by the balance between two competing effects: electronic (favoring heavier lanthanides) and solvation (generally favoring the lighter lanthanides).