A symmetric structural model for Acid sensing ion channel-1: Transmembrane domain dynamics and Implications to Gating

Acid sensing ion channels (ASICs) are cation-selective neuronal membrane channels, activated by H+ binding upon decrease in extracellular pH. The mechanistic and structural details of channel activation and ion permeation in ASICs are only partially understood. The only known crystal structure for ASICs is in the desensitized, non-conducting state, and the open and closed structures remain unsolved. The crystal structure reveals ASIC1 to be a trimer with 3-fold symmetry, but reports significant asymmetry in the transmembrane (TM) region, suggested to be induced by crystal lattice contacts, hence restricting further hypotheses about TM behavior. In order to enable a study of TM domain dynamics, we sought to derive models from the crystal structure, where this asymmetry was corrected using a simulation based approach. We designed a model target based on normal mode analysis, and employed targeted molecular dynamics to generate the initial model from the crystal structure followed by a series of simulations to equilibrate the structure. The resulting model, though starting with nearly straight TM helices, exhibits kinks as the simulations proceed, suggesting dynamic hinges in the TM pore, which could be participants in gating. Observations about channel behavior from these models show consistence with experimental data. An interesting revelation from the model is the identification of a possible gating region near the cytoplasmic end of the TM pore constituted of highly hydrophobic residues. Overall the study reveals several details about the putative cation permeation pathway in ASICs and also provides a symmetric structural model to test further hypotheses on ASIC channel function.