Bulletin of the American Physical Society
APS March Meeting 2021
Volume 66, Number 1
Monday–Friday, March 15–19, 2021; Virtual; Time Zone: Central Daylight Time, USA
Session E08: Structure and Dynamics of Charged Polymers
8:00 AM–11:00 AM,
Tuesday, March 16, 2021
Sponsoring
Units:
DPOLY DSOFT DCOMP DBIO
Chair: Charles Collier, Oak Ridge National Lab; Bradley Lokitz, Oak Ridge National Lab
Abstract: E08.00008 : A computational approach to characterize gating in ion channels*
9:24 AM–9:36 AM
Live
Presenter:
Carlo Guardiani
(Department of Mechanical and Aerospace Engineering, University of Rome La Sapienza)
Authors:
Carlo Guardiani
(Department of Mechanical and Aerospace Engineering, University of Rome La Sapienza)
Flavio Costa
(Department of Mechanical and Aerospace Engineering, University of Rome La Sapienza)
Alberto Giacomello
(Department of Mechanical and Aerospace Engineering, University of Rome La Sapienza)
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.
*This project has received funding from the European
Research Council (ERC) under the European Union's
Horizon 2020 research and innovation programme
(grant agreement No. 803213).
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