A computational approach to characterize gating in ion channels

Our contribution concerns gating, i.e. the
ability of ion channels to pass from closed to
open state in response to a stimulus. Since this
process occurs on a timescale not reachable
by MD simulations, we employed Targeted MD, a
technique that imposing a bias on RMSD, steers
the molecule between fixed end states. The
analysis of the sequence of contact formation
and breakdown events then yields a detailed
characterization of the gating mechanism.
This approach can be integrated by an analysis
of dynamical communication pathways portraying
the protein as a graph with edge weights based on
correlation coefficients. We tested this approach
on two systems of biomedical interest, the hERG
and CRAC channels. We showed that in hERG, at
variance with domain-swapped K+ channels, gating
relies on a intra-subunit communication from loop
L45 to helix S6. The study of CRAC, on the other
hand, revealed a hydrophobic gating mechanism where
pore helix rotation changes the solvent accessible
area of the pore inducing the formation of a vacuum
bubble that prevents water and ion flow.