Effects of Electric Field on Channel Proteins Through Dipole Perturbation and Network of Signal Transmission

Abstract

Kv1.2 voltage-gated and MlotiK1 cyclic nucleotide-gated K+ channels belong to the family of tetrameric cation channels and share a similar protein fold in the transmembrane region. Kv1.2 channel is activated by the changes in the transmembrane potential, while MlotiK1 channel is activated upon the binding of cyclic nucleotides to its intracellular domain. We use a perturbation-based markovian transmission model [Lu and Liang,PLoS Comp. Biol. 2009] to study allosteric activation pathways in both channels. The initial perturbation on residues, e.g., ligand binding or conformational change, is converted to flow of probability, which allows studying of the time-course of signal transmission and propagation of probability flow through the protein molecule. As dipoles in channel proteins respond to the external electric field, change in energy and introduction of torque arise for individual residues. We postulate residues that experience large energy change and torque are those responding first to the membrane depolarization in ion channels. To identify regions of initial perturbation, we build structural models by embedding channel proteins in the POPC lipid bilayer, with surrounding slabs of water molecules on both sides of the membrane. Our calculations identified S1 helix of voltage sensing domain, linker, and filter regions in Kv1.2 channel, as well as helix S1 and linker in MlotiK1 channel as the regions of initial response, as they contain the majority of strongly polarizable dipoles. Our results show that dipole perturbation results in a strong signal transmittion to the charged arginine residues of S4 in Kv1.2, whereas no significant signal transmission is observed under the same perturbation for MlotiK1 channel. This suggests dipole perturbation is a mechanism how voltage gated channel proteins respond to external electric field. This mechanism, however, is not employed by ligand-gated channels.