| Abstract
| - Trivalent lanthanide cations are extensively being used in biochemical experiments to probevarious dication-binding sites in proteins; however, the factors governing the binding specificity of lanthanidecations for these binding sites remain unclear. Hence, we have performed systematic studies to evaluatethe interactions between La3+ and model Ca2+- and Mg2+-binding sites using density functional theorycombined with continuum dielectric methods. The calculations reveal the key factors and correspondingphysical bases favoring the substitution of trivalent lanthanides for divalent Ca2+ and Mg2+ in holoproteins.Replacing Ca2+ or Mg2+ with La3+ is facilitated by (1) minimizing the solvent exposure and the flexibility ofthe metal-binding cavity, (2) freeing both carboxylate oxygen atoms of Asp/Glu side chains in the metal-binding site so that they could bind bidentately to La3+, (3) maximizing the number of metal-bound carboxylategroups in buried sites, but minimizing the number of metal-bound carboxylate groups in solvent-exposedsites, and (4) including an Asn/Gln side chain for sites lined with four Asp/Glu side chains. In proteinsbound to both Mg2+ and Ca2+, La3+ would prefer to replace Ca2+, as compared to Mg2+. A second Mg2+-binding site with a net positive charge would hamper the Mg2+ → La3+ exchange, as compared to therespective mononuclear site, although the La3+ substitution of the first native metal is more favorable thanthe second one. The findings of this work are in accord with available experimental data.
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