An Improved Method for Modeling Voltage-Gated Ion Channels at Atomic Accuracy Applied to Human Ca_v Channels

Voltage-gated ion channels (VGICs) are associated with hundreds of human diseases. To date, 3D structural models of human VGICs have not been reported. We developed a 3D structural integrity metric to rank the accuracy of all VGIC structures deposited in the PDB. The metric revealed inaccuracies in structural models built from recent single-particle, non-crystalline cryo-electron microscopy maps and enabled the building of highly accurate homology models of human Ca_v channel α₁ subunits at atomic resolution. Human Ca_v Mendelian mutations mostly located to segments involved in the mechanism of voltage sensing and gating within the 3D structure, with multiple mutations targeting equivalent 3D structural locations despite eliciting distinct clinical phenotypes. The models also revealed that the architecture of the ion selectivity filter is highly conserved from bacteria to humans and between sodium and calcium VGICs. Martinez-Ortiz et al. develop an accuracy metric for structural models of voltage-gated ion channels based on the conservation of a core functional cluster of amino acids. The significance of the method is its ability to reveal and correct subtle modeling errors and refine low-resolution VGICs to atomic accuracy.