Factors allowing small monovalent Li to displace Ca in proteins.

Because Li and Ca differ in both charge and size, the possibility that monovalent Li could dislodge the bulkier, divalent Ca in Ca proteins had not been considered. However, our recent density functional theory/continuum dielectric calculations predicted that Li could displace the native Ca from the C2 domain of cytosolic PKCα/γ. This would reduce electrostatic interactions between the Li-bound C2 domain and the membrane, consistent with experimental studies showing that Li can inhibit the translocation of cytoplasmic PKC to membranes. Besides the trinuclear Ca-site in the PKCα/γ C2 domain, it is not known whether other Ca-sites in human proteins may be susceptible to Li substitution. Furthermore, it is unclear what factors determine the outcome of the competition between divalent Ca and monovalent Li. Here we show that the net charge of residues in the first and second coordination shell is a key determinant of the selectivity for divalent Ca over monovalent Li in proteins: neutral/anionic Ca-carboxylate sites are protected against Li attack. They are further protected by outer-shell Asp/Glu and the protein matrix rigidifying the Ca-site or limiting water entry. In contrast, buried, cationic Ca-sites surrounded by Arg/Lys, which are found in the C2 domains of PKCα/γ, as well as certain synaptotagmins, are prone to Li attack.