Predicting Allosteric Pathways for Activation of K+ Channels by Perturbation Based Markovian Transmission Model

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. Activation of both channels results in a passive flow of K+ ions, although Kv1.2 channel is activated by changes in transmembrane potential, while MlotiK1 channel is activated by the binding of cyclic nucleotides to the intracellular domain. Here we use a perturbation-based markovian transmission (PMT) model to study and compare allosteric activation pathways in Kv1.2 and MlotiK1 channels. With this model, the initial perturbation 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. We found that for the allosteric signal transmission to take place in Kv1.2, all ionizable residues in the TM region must be perturbed, while the perturbation of the ionizable residues on the S4 helix of Kv1.2 alone did not result in signal propagation. Furthermore, perturbation of ionizable residues in the TM region of cyclic nucleotide-gated MlotiK1 did not result in detectable signal transmission, while perturbation of the resolved part of the C-linker and the S2-S3 loop together initiate a signal transmission process, which went from the intracellular side of the channel to the extracellular side and to the filter and P-loop region. Our result showed that PMT model can distinguish different activation mechanisms in channels sharing similar fold. We have also predicted residues important for the allosteric signal transmission in Kv1.2 and MlotiK1 channels. Based on our calculations, we identified important structural elements in activation of MlotiK1 channel. In addition, we show that most of the on-pathway residues are aromatic residues in both channels.