![]() Ln 3+ also resembles more alkaline earth metal dications than the respective transition metal counterparts, as the bonding with the former is essentially ionic. Lanthanides and Ca 2+ behave as “hard” acids with high affinity to “hard” bases containing oxygen, rather than “soft” bases comprising nitrogen, phosphorus, and sulfur. ![]() Notably, the conserved Glu at the last position of the EF-hand binding loop (Glu-12) binds Ca 2+ in a bidentate fashion via both carboxylate oxygens, whereas the other Asp/Glu residues bind Ca 2+ monodentately, employing one of the carboxylate oxygens ( Figure 1).Įmploying Ln 3+ (this includes La 3+ from now on unless specified) in probing Ca 2+ binding sites, which have limited number of chemical properties to be examined by experimental techniques, stems from the ability of the lanthanides to closely mimic some characteristics of the native metal. ![]() The binding site is characterized by a pentagonal bipyramidal geometry. Aspartate/glutamate (Asp/Glu) and asparagine/glutamine (Asn/Gln) side chains as well as backbone carbonyls from the loop ligate the Ca 2+ ion, which often retains a bound water molecule. The canonical EF hand motif, which is highly selective for Ca 2+ over Mg 2+ and other physiological metal cations, consists of a 12-residue calcium-binding loop surrounded by two helices creating a signature helix–loop–helix motif. These proteins contain Ca 2+ binding sites, most of which belong to the so-called EF-hand motif family. The latter (parvalbumin, calmodulin D, calcineurin, recoverin, troponin C, cadherin, and S100P) are involved in a plethora of physiological processes such as muscle contraction, vision, cell cycle regulation, brain cortex and cerebellum modulation, and microtubule organization. Lanthanum (La 3+) and its fellow lanthanides (Ln 3+) have been extensively used to study the structure and biochemical properties of vast number of metalloproteins, the calcium-signaling/buffering proteins in particular. 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). 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. 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. 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 present research offers a systematic investigation of the ability of the entire Ln 3+ series to substitute for Ca 2+ in biological systems. The characteristics of lanthanides within the lanthanide series are similar, but not identical. Lanthanides, the 14 4f-block elements plus Lanthanum, have been extensively used to study the structure and biochemical properties of metalloproteins.
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