Parent dataset and code from: Atomistic Mechanisms of the regulation of small conductance Ca 2+ -activated K + channel (SK2) by PIP2

Small conductance Ca 2+ -activated K + channels (SK, K Ca 2) are gated
solely by intracellular microdomain Ca 2+. The channel has emerged as a
therapeutic target for cardiac arrhythmias. Calmodulin (CaM) interacts
with the CaM binding domain (CaMBD) of the SK channels, serving as the
obligatory Ca 2+ sensor to gate the channels. In heterologous expression
systems, phosphatidylinositol 4,5-bisphosphate (PIP2) coordinates with CaM
in regulating SK channels. However, the roles and mechanisms of PIP2 in
regulating SK channels in cardiomyocytes remain unknown. Here,
optogenetics, magnetic nanoparticles, combined with Rosetta structural
modeling and molecular dynamics (MD) simulations revealed the atomistic
mechanisms of how PIP2 works in concert with Ca 2+ -CaM in the SK channel
activation. Our computational study affords evidence for the critical role
of the amino acid residue R395 in the S6 transmembrane domain, which is
localized in propinquity to the intracellular hydrophobic gate. This
residue forms a salt bridge with residue E398 in the S6 transmembrane
domain from the adjacent subunit. Both R395 and E398 are conserved in all
known isoforms of SK channels. Our findings suggest that the binding of
PIP2 to R395 residue disrupts the R395:E398 salt bridge, increasing the
flexibility of the transmembrane segment S6 and the activation of the
channel. Importantly, our findings serve as a new platform for testing
structural-based drug designs for therapeutic inhibitors and activators of
the SK channel family. The study is timely since inhibitors of
SK channels are currently in clinical trials to treat atrial
arrhythmias.