Calcium binding and permeation in TRPV channels: insights from molecular dynamics simulations

Some calcium channels selectively permeate Ca ²⁺ , despite the high concentration of monovalent ions in the surrounding environment, which is essential for many physiological processes. Without atomistic and dynamical ion permeation details, the underlying mechanism of Ca ²⁺ selectivity has long been an intensively studied, yet controversial, topic. This study takes advantage of the homologous Ca ²⁺ -selective TRPV6 and non-selective TRPV1 and utilizes the recently solved open-state structures and a newly developed multi-site calcium model to investigate the ion binding and permeation features in TRPV channels by molecular dynamics simulations. Our results revealed that the open-state TRPV6 and TRPV1 show distinct ion-binding patterns in the selectivity filter, which lead to different ion permeation features. Two Ca ²⁺ ions simultaneously bind to the selectivity filter of TRPV6 compared with only one Ca ²⁺ in case of TRPV1. Multiple Ca ²⁺ binding at the selectivity filter of TRPV6 permeated in a concerted manner, which could efficiently block the permeation of Na ⁺ . Cations of various valences differentiate between the binding sites at the entrance of the selectivity filter in TRPV6. Ca ²⁺ preferentially binds to the central site with a higher probability of permeation, repelling Na ⁺ to a peripheral site. Therefore, we believe that ion binding competition at the selectivity filter of calcium channels, including the binding strength and number of binding sites, determines Ca ²⁺ selectivity under physiological conditions. Additionally, our results showed that pore helix flexibility and the cytosolic domain of TRPV channels regulate ion permeability.