Conductance Mechanism of Mutant K+ Channels

Abstract

K+ channels play a crucial role in the life of cells: ionic currents through K+ channels establish the membrane voltage in all cells and terminate action potentials in excitable cells. K+ channels have a conserved functional core - selectivity filter (SF) - that consists of successive K+ binding sites lined with carbonyl groups and serves as a primary regulator of K+ channels activity. K+ channels are characterized by high conductivity coupled with high selectivity. Despite decades of research, the exact microscopic events leading to such highly efficient ion permeation are still not known. Based on molecular dynamics simulations of various potassium channels (such as KcsA, MthK, and others), we have proposed a ‘direct knock-on’ ion permeation mechanism, where water-free permeation and formation of direct ion-ion contacts in the SF provide high K+ conductance, while being intrinsically ion selective. This direct knock-on mechanism was confirmed by several experimental observations. Recently, the direct knock-on model has been challenged by new experimental data on SF mutants of the KcsA K+ channel, that were able to maintain high selectivity, while the water-free ion permeation was seemingly disrupted. Here, we use molecular dynamics simulations to study the permeation mechanism of these SF mutants. We show that the SF mutants undergo conformational changes that are incompatible with the permeation mechanism of wild-type channels. Our results are in good agreement with experimental data, thus reinforcing the direct knock-on model as a likely conduction mechanism in K+ channels.