Electrostatics effects on Ca2+ binding and conformational changes in EF-hand domains: Functional implications for EF-hand proteins

• N-Cam mutant Q41L-K75I does not change conformation upon Ca2+ binding, similar to Calbindin D9k.
• Charge state of polar residues 41 and 75 affects N-Cam Ca2+ binding and conformational change.
• Charge state of polar residues 41 and 75 affects Ca2+ free N-Cam stability and molecular dynamics.
• Dynamics of Ca2+ sensor EF-hand domains may play important role in the multifunction of EF-hand proteins.

Mutations of Gln41 and Lys75 with nonpolar residues in the N-terminal domain of calmodulin (N-Cam) revealed the importance of solvation energetics in conformational change of Ca2+ sensor EF-hand domains. While in general these domains have polar residues at these corresponding positions yet the extent of their conformational response to Ca2+ binding and their Ca2+ binding affinity can be different from N-Cam. Consequently, here we address the charge state of the polar residues at these positions. The results show that the charge state of these polar residues can affect substantially the conformational change and the Ca2+ binding affinity of our N-Cam variants. Since all the variants kept their conformational activity in the presence of Ca2+ suggests that the differences observed among them mainly originate from the difference in their molecular dynamics. Hence we propose that the molecular dynamics of Ca2+ sensor EF-hand domains is a key factor in the multifunctional aspect of EF-hand proteins.

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