Dynamics of AKAP/Calmodulin complex is largely driven by ionic occupancy state

AKAP79/150 is a scaffold protein found in dendritic spines and other neuronal compartments. It localizes and regulates phosphorylation by protein kinase A and C and is, in turn regulated by $C{a}^{2+}$, mediated by Calmodulin (CaM). Thus, the interaction of AKAP79/150 with CaM is of biological interest. A 2017 study used a peptide cross linking coupled to mass spectrometry (XLMS) to identify the CaM binding site on AKAP79/150 and subsequently solved an X-ray crystallography structure of CaM in complex with a short helical AKAP79/150 peptide. The XRD structure revealed an unusual mixed ionic occupancy state of CaM as bound to the AKAP79/150 peptide. In this molecular dynamics-based study, we have explored the motional modes of the CaM-AKAP helix complex under three ionic occupancy conditions. Our results indicate that the dynamics of this CaM backbone is largely dominated by the ionic occupancy state. We find that binding of the AKAP79/150 peptide to CaM is not preferentially stabilized in energetic terms in the Ca²⁺ state as compared to apo. However, the Mg²⁺ state is destabilized energetically as compared to the apo state. In addition, in the Ca²⁺ state, the AKAP79/150 peptide appears to be preferentially stabilized by additional hydrogen bonds. Our simulations suggest that further structural biology studies should be carried out, with a focus on driving the system equilibrium to full $C{a}^{2+}$ occupancy. NMR studies may be able to capture conformational states which are not seen in crystals.