Figure 9.

Free Energy Landscape of CaM Illustrating the Coupled Equilibrium Shift Mechanism

Based on our findings and previous experimental data (Malmendal et al., 1999), we suggest that the different states of CaM are in a dynamic equilibrium and, in particular, that shifts in the equilibrium are coupled between the two domains. The binding of Ca²⁺ ions initially shifts the equilibrium from the apo to the holo state (Ca²⁺-CaM). Binding of the MLCK ligand takes place first at the CTD, which assumes the bound conformation. This event increases the likelihood of sampling high-affinity substates in NTD (highlighted in yellow), which eventually leads to binding and an equilibrium shift in this domain.