Lanthanides as Calcium Mimetic Species in Calcium-Signaling/Buffering Proteins: The Effect of Lanthanide Type on the Ca2+/Ln3+ Competition

Abstract

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 Ln3+ series to substitute for Ca2+ 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” La3+/Ln3+ and “native” Ca2+, and La3+ − Ln3+ within the lanthanide series. The calculations performed reveal that the major determinant of the Ca2+/Ln3+ 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 Ln3+ with respect to its Ca2+ 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 Ln3+ over Ca2+ selectivity, whereas it is the opposite for sites with overall charge of −1. Within the series, the competition between La3+ and its fellow lanthanides is determined by the balance between two competing effects: electronic (favoring heavier lanthanides) and solvation (generally favoring the lighter lanthanides).

Electrostatic interactions – key determinants of the metal selectivity in La3+ and Ca2+ binding proteins

“…The competition between La 3+ /Ln 3+ and Ca 2+ in calcium-binding proteins has been studied before using both experimental and computational techniques as the lanthanum/lanthanide substitution of the native calcium cation appears beneficial in determining the structural characteristics of the host Ca 2+ proteins. 21,28–41 Notably, the present study deepens our understanding about the basic principles governing the Ca 2+ /La 3+ competition from the perspective of lanthanum-binding proteins.…”

In Vivo Evaluation of Innovative Gadolinium-Based Contrast Agents Designed for Bioimaging Applications

“…Recently, it was reported that Gd 3+ is a lanthanide ion that could be considered a calcium mimetic in calcium-signaling/buffering proteins [ 44 ]. Considering that Gd 3+ inhibits Ca-dependent enzymes and voltage-activated channels, several physiological consequences could occur.…”

Systematic review of the osteogenic effect of rare earth nanomaterials and the underlying mechanisms

“…Y 2 O 3 NPs, for instance, localize to acidifying intracellular lysosomes after they are taken up by BMSCs, and they undergo dissolution and transformation from Y 2 O 3 NPs to Y 3+ [ 29 ]. Most RE ions have biological properties similar to those of Ca 2+ and exhibit the ability to structurally or functionally replace Ca 2+ to exert positive or negative effects on bone regeneration [ 30 ].…”