Calcium (Ca 2+ ) permeation mechanisms across diverse ion channels remain elusive at the atomic level. Here, we employ computational simulations to elucidate the distinct strategies governing Ca 2+ selectivity and permeation in ryanodine receptors (RyR), TRPV channels, and voltage-gated Ca 2+ channels (Ca V ). Our analysis reveals that wide-pore RyRs utilize a negatively charged vestibule to enable divalent ion selectivity via charge/space competition, while narrow-pore channels (e.g., TRPV and Ca V ) deploy elongated selectivity filters with precisely tuned binding sites to support coordinated multi-ion transport. Critically, highly selective channels (TRPV6 and Ca V ) exploit a three-ion knock-on mechanism to optimize both permeability and cation selectivity. Notably, we identify a significant discrepancy between the permeability ratios derived from reversal potential measurements (GHK equation) and those obtained from molecular dynamics/Brownian dynamics simulations for certain simplified ion channel models. This inconsistency demonstrates that the Ca 2+ selectivity in some channels may have been overestimated in previous electrophysiological studies, necessitating a reevaluation of ion selectivity in calcium-signaling research. This issue may exist in other single-file multi-occupancy ion channels as well.
Xue et al. (Sun,) studied this question.