Protein Ca-Sites Prone to Sr Substitution: Implications for Strontium Therapy.

Strontium (Sr), an alkali metal with properties similar to calcium, in the form of soluble salts is used to treat osteoporosis. Despite the information accumulated on the role of Sr as a Ca mimetic in biology and medicine, there is no systematic study of how the outcome of the competition between the two dications depends on the physicochemical properties of (i) the metal ions, (ii) the first- and second-shell ligands, and (iii) the protein matrix. Specifically, the key features of a Ca-binding protein that enable Sr to displace Ca remain unclear. To address this, we studied the competition between Ca and Sr in protein Ca-binding sites using density functional theory combined with the polarizable continuum model. Our findings indicate that Ca-sites with multiple strong charge-donating protein ligands, including one or more bidentately bound Asp/Glu that are relatively buried and rigid are protected against Sr attack. On the other hand, Ca-sites crowded with multiple protein ligands may be prone to Sr displacement if they are solvent-exposed and flexible enough so that an extra backbone ligand from the outer shell can bind to Sr. In addition, solvent-exposed Ca sites with only a few weak charge-donating ligands that can rearrange to fit the strontium's coordination requirements are susceptible to Sr displacement. We provide the physical basis of these results and discuss potential novel protein targets of therapeutic Sr.