BPS2026 – Molecular dynamics reveal mechanistic divergence between the two pores of Fluc

The introduction of fluoridated water has been one of the most impactful public health interventions, contributing not only to bone health and dental protection but also functioning as a potent antimicrobial agent. The effectiveness of fluoride has been challenged by the discovery that microorganisms possess specialized transport systems to eliminate intracellular fluoride. Identified about a decade ago, the two key players are CLC F and Fluc, which represent distinct structural solutions to the same evolutionary problem. While CLC F shares structural and mechanistic features with the well-studied CLC family of chloride channels and antiporters, Fluc represents a completely novel protein family that has captivated the scientific community with its unique properties. Fluc is the fastest and most selective ion channel reported to date; even a modest reduction in its selectivity for fluoride over chloride would compromise membrane potential. Remarkably, its extraordinary performance arises from an antiparallel homodimeric assembly that creates two independent, asymmetric fluoride-conducting pores rather than a central shared pore. Crystal structures have also revealed a central cation, most likely sodium, whose precise role in channel stability or function remains unresolved. In this work, we employed long-timescale electrophysiology-based molecular dynamics simulations to investigate the molecular mechanism of fluoride permeation in Fluc. Our results reveal a striking functional asymmetry between the two pores, each operating through a distinct mechanistic pathway. Furthermore, we observed dynamic movement of the central sodium ion, suggesting it may play a critical role in modulating conductivity. To our knowledge, this is the first demonstration that a single Fluc dimer can support two mechanistically distinct transport routes. These findings not only provide new insight into the enigmatic features of Fluc but also suggest strategies for designing transporters with dual selectivity by exploiting structural asymmetry.