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).

The emergence of multidrug-resistant (MDR) microorganisms combined with the ever-draining antibiotic pipeline poses a disturbing and immensely growing public health challenge that requires a multidisciplinary approach and the application of novel therapies aimed at unconventional targets and/or applying innovative drug formulations. Hence, bacterial iron acquisition systems and bacterial Fe^2+/3+-containing enzymes have been identified as a plausible target of great potential. The intriguing “Trojan horse” approach deprives microorganisms from the essential iron. Recently, gallium’s potential in medicine as an iron mimicry species has attracted vast attention. Different Ga³⁺ formulations exhibit diverse effects upon entering the cell and thus supposedly have multiple targets. The aim of the current study is to specifically distinguish characteristics of great significance in regard to the initial gallium-based complex, allowing the alien cation to effectively compete with the native ferric ion for binding the siderophores pyochelin and pyoverdine secreted by the bacterium P. aeruginosa. Therefore, three gallium-based formulations were taken into consideration: the first-generation gallium nitrate, Ga(NO₃)₃, metabolized to Ga³⁺-hydrated forms, the second-generation gallium maltolate (tris(3-hydroxy-2-methyl-4-pyronato)gallium), and the experimentally proven Ga carrier in the bloodstream—the protein transferrin. We employed a reliable in silico approach based on DFT computations in order to understand the underlying biochemical processes that govern the Ga³⁺/Fe³⁺ rivalry for binding the two bacterial siderophores.