Insights into the mechanisms of K+ permeation in K+-channels from computer simulations

Victoria Oakes, Simone Furini, Carmen Domene

Research output: Contribution to journalArticle

Abstract

Ion permeation, selectivity, and the behavior of the K + channel selectivity filter have been studied intensively in the previous two decades. The agreement among multiple approaches used to study ion flux in K + channels suggests a consensus mechanism of ion permeation across the selectivity that has been put to the test in recent years with the proposal of an alternative way by which ions can cross the selectivity filter of K + channels via direct Coulomb repulsion between contacting cations. Past experimental work by Zhou and MacKinnon (J. Mol. Biol. 2004, 338, 839) showed that mutation of the site S4 reduces the total occupancy of the selectivity filter to less than two ions on average by lowering the occupancy of the S2-S4 configuration without changing the S1-S3 configuration much, and this reduction of occupancy means that ion configurations different from the ones involved in the canonical mechanism are likely to be involved. At that time, calculations using complicated kinetic networks to relate occupancy to conduction did not provide deeper insight into the conduction mechanism. Here, to help solve this enigma, umbrella sampling simulations have been performed to evaluate the potential of mean force of two KcsA mutant channels where the S4 site is substituted. Our new results provide insights into the significance of threonine in this position, revealing the effect of substitution on the alternate mechanisms of conduction proposed, involving either water or vacant sites.

Original languageEnglish
Pages (from-to)794-799
JournalJournal of Chemical Theory and Computation
Volume16
Issue number1
Early online date6 Dec 2019
DOIs
Publication statusPublished - 14 Jan 2020

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