Dissecting current rectification through asymmetric nanopores

Rectification, the tendency of bidirectional ionic conductors to favor ion flow in a specific direction, is an intrinsic property of many ion channels and synthetic nanopores. Despite its frequent occurrence in ion channels and its phenomenological explanation using Eyrings rate theory, a quantitative relationship between the rectified current and the underlying ion-specific and voltage-dependent free energy profile has been lacking. In this study, we designed nanopores in which potassium and chloride current rectification can be manipulated by altering the electrostatic pore polarity. Using molecular dynamics-based free energy simulations, we quantified voltage-dependent changes of free energy barriers in six ion-nanopore systems. Our results illustrate how the energy barriers for inward and outward fluxes become unequal in the presence of an electromotive driving force, leading to varying degrees of rectification for cation and anion currents. This work establishes a direct link between equilibrium potential of mean force and current rectification rate and demonstrates that rectification caused by energy barrier asymmetry depends on the nature of the permeating ion, can be tuned by pore polarity, does not require ion binding sites, conformational flexibility, or specific pore geometry, and, as such, may be widespread among ion channels. Statement of significanceIn many ion channels, ions flow faster in one direction than the other, even under equal magnitude of driving forces. This phenomenon, known as rectification, often arises as an intrinsic biophysical property of the channel pore and has significant physiological implications. Our molecular dynamics simulations provide a unified framework to dissect the free energy profiles that underpin current rectification. This approach has broad applications in the field of ion channel biology and material design.