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 multisite 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 the 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.