Heavy Metal Directly Blocks Potassium Channels: An Experimental and Theoretical Approach

Modeling the interaction of heavy-metal cations with ion channels remains challenging due to their strong electrostatics, complex coordination chemistry, and the need to probe permeation under driven conditions. Here, we combine electrophysiology and molecular dynamics simulations to investigate how inorganic lead (Pb²⁺) and mercury (Hg²⁺) inhibit potassium (K⁺) channels. Although both metals are well-known environmental toxicants, the molecular basis of their direct interactions with K⁺ channels remains incompletely understood. Patch-clamp recordings across structurally diverse K⁺ channel families show that Pb²⁺ and Hg²⁺ suppress K⁺ currents, with Hg²⁺ producing a more potent blockade, while simulations of the KcsA channel reveal preferential binding of both ions to conserved acidic residues in the extracellular vestibule, which disrupts K⁺ occupancy in the selectivity filter and impairs conduction. Effective free-energy landscapes identify metal-specific vestibular binding basins whose topologies correlate with experimentally observed blocking behavior. Together, these results indicate that Pb²⁺ and Hg²⁺ act as outer-pore blockers through localized electrostatic and geometric interactions, analogous to classical divalent cation blockers. More broadly, this work provides a transferable computational framework for studying multivalent ion blockers in K⁺ channels and clarifies which mechanistic observables remain robust despite force-field limitations and nonequilibrium simulation regimes.