Allosteric model of calmodulin with hemiconcerted conformational transitions.

<p>Calmodulin has 4 calcium-binding sites (A, B, C, D) corresponding to one EF-hand each, and organised in two globular domains, N-lobe (pink) and C-lobe (light blue). Green arrows represent conformational transitions, red arrows represent calcium binding. Each binding site is modelled as a subunit that has access to two conformational states: open, high-affinity R state, and closed, low-affinity T state. Subunits on the same lobe are constrained to be in the same state, but the two lobes are allowed to be in different states. When no ligand is present, 4 possible configurations (TT, RT, TR, RR) coexist in thermodynamic equilibrium. A lobe that undergoes a T-to-R transition increases its affinity for calcium. Under these assumptions, it follows from classical linkage theory that ligand binding shifts the conformational equilibrium towards the open form, by stabilising the higher-affinity R state. Cooperativity is predicted as an emergent property.