Structural and functional characterization of Caenorhabditis elegans cyclic GMP-activated channel TAX-4 via molecular dynamics simulations

Cyclic nucleotide-gated (CNG) ion channels are crucial to the intracellular calcium dynamics in neurons and other sensory cells, in several organisms. Mutations in CNG genes are linked to various dysfunctions and diseases. In this work, we propose a theoretical investigation of the structural and functional properties of wild-type TAX-4, a non-selective CNG ion channel, expressed in various sensory neurons of Caenorhabditis elegans, and involved in the permeation of monovalent and multivalent cations. Using a recent cryo-electron microscopy structure of the open state of the channel as the starting conformation, we conduct all-atom molecular dynamics simulations of the full-length channel in a membrane/water/ions system, both in the cGMP-bound and unbound conformations. Several channel structural descriptors are examined and a first-level functional annotation is carried out, on the microsecond time scale. A comparison with the available experimental data on TAX-4 and human homologues allows us to assign the simulated bound and unbound models as the pre-open and closed conformations of TAX-4, respectively. Comparisons between the bound and unbound conformations enable us to suggest key conformational changes underlying the binding-to-gating transition.