Opposing Intermolecular Tuning of Ca²⁺ Affinity for Calmodulin by Neurogranin and CaMKII Peptides

We investigated the impact of bound calmodulin (CaM)-target structure on the affinity of calcium (Ca²⁺) by integrating coarse-grained and all-atomistic simulations with nonequilibrium physics. We focused on binding between CaM and two specific targets, Ca²⁺/CaM-dependent protein kinase II (CaMKII) and neurogranin (Ng), as they both regulate CaM-dependent Ca²⁺ signaling pathways in neurons. It was shown experimentally that Ca²⁺/CaM (holoCaM) binds to the CaMKII peptide with overwhelmingly higher affinity than Ca²⁺-free CaM (apoCaM); the binding of CaMKII peptide to CaM in return increases the Ca²⁺ affinity for CaM. In contrast, Ng peptide binds to apoCaM or holoCaM with binding affinities of the same order of magnitude. We discovered the molecular underpinnings of altered affinity of Ca²⁺ for CaM in the presence of Ng or CaMKII from the the distinctive structural difference in the complexes of apoCaM-Ng and holoCaM-CaMKII, which we speculate delineates the importance of CaM’s progressive mechanism of target binding on its Ca²⁺ binding affinities.