The family of small-conductance (SK) ion channels is composed of four members (SK1, SK2, SK3, and SK4) involved in neuron-firing regulation. The gating of these channels depends on the intracellular Ca2+ concentration, and their sensitivity to this ion is provided by calmodulin (CaM). This protein binds to a specific region in SK channels known as the calmodulin-binding domain (CaMBD), an event which is essential for their gating. While CaM-binding domains are typically disordered in the absence of CaM, the SK2 channel subtype displays a small pre-folded alpha helical region in its CaMBD even if CaM is not present. This small helix is known to turn into a full alpha-helix upon CaM binding, although the molecular-level details for this conversion are not fully understood yet. In this work, we offer new insights on this physiologically relevant process by means of enhanced sampling, atomistic Hamiltonian replica exchange molecular dynamics simulations, providing a more detailed understanding of CaM binding to this target. Our results show that CaM is necessary for inducing a full alpha-helix along the SK2 CaMBD through hydrophobic interactions with V426 and L427. However, it is also necessary that W431 does not compete for these interactions; the role of the small pre-folded alpha-helix in the SK2 CaMBD would be to stabilize W431 so that this is the case. Competing Interest Statement The authors have declared no competing interest. Footnotes * https://github.com/BilbaoComputationalBiophysics/Articles-Supporting_info/tree/CaM_induced_helix_in_SK2...

Molecular dynamics simulations of the calmodulin-induced alpha-helix in the SK2 calcium-gated potassium ion channel

10.1101/2022.11.02.514819