Multi-ion free energy landscapes underscore the microscopic mechanism of ion selectivity in the KcsA channel

Abstract

Potassium (K+) channels are transmembrane proteins that passively and selectively allow K+ ions to flow through them, after opening in response to an external stimulus. One of the most critical functional aspects of their function is their ability to remain very selective for K+ over Na+ while allowing high-throughput ion conduction at a rate close to the diffusion limit. Classically, it is assumed that the free energy difference between K+ and Na+ in the pore relative to the bulk solution is the critical quantity at the origin of selectivity. This is the thermodynamic view of ion selectivity. An alternative view assumes that kinetic factor play the dominant role. Recent results from a number of studies have also highlighted the great importance of the multi-ion single file on the selectivity of K+ channels. The data indicate that having multiple K+ ions bound simultaneously is required for selective K+ conduction, and that a reduction in the number of bound K+ ions destroys the multi-ion selectivity mechanism utilized by K+ channels. In the present study, multi-ion potential of mean force molecular dynamics computations are carried out to clarify the mechanism of ion selectivity in the KcsA channel. The computations show that the multi-ion character of the permeation process is a critical element for establishing the selective ion conductivity through K+-channels.

Ion channels and ion selectivity

“…Theoretical and computational analysis has led to a better understanding of the role of conformational flexibility and structural strain energy on ion selectivity (Noskov et al, 2004; Yu et al, 2010). Additional kinetic factors related to the multi-ion nature of the pore appear to be also important for the selectivity of K + channels (Medovoy et al, 2016). Lastly, the selectivity of the latter appears to be also entangled with the conformational plasticity and relative stability of the conductive and non-conductive form of the pore (Roux et al, 2011).…”

“…Nevertheless, even though computational studies offer a great complement to the information from X-ray crystallography and functional measurements, it is nonetheless important to keep in mind that the results can be sensitive to the inaccuracies in the force field used to generate MD simulations (Jensen et al, 2013). Over the years there have been numerous studies of the K + channel (Åqvist and Luzhkov, 2000; Bernèche and Roux, 2001; Noskov et al, 2004; Roux, 2005; Furini and Domene, 2009; Thompson et al, 2009; Egwolf and Roux, 2010; Kim and Allen, 2011; Kopfer et al, 2014; Medovoy et al, 2016), and more recently of Na + channels (Chakrabarti et al, 2013; Ulmschneider et al, 2013; Bagneris et al, 2015; Ing and Pomes, 2016; Naylor et al, 2016). …”

“…Therefore, because of its highly concerted nature, ion conduction through the narrow selectivity filter of K + channels is a multi-ion process that involves the evolution of several dynamical variables that are tightly coupled. Interesting, a computational study showed that when one allows the two outer ions in the single file K + /W/ K + /W/ K + , or K + /W/ Na + /W/ K + , to sample a Boltzmann-weighted average of their available positions then the central site S 2 is not selective for K + or Na + (Medovoy et al, 2016). This is truly an unexpected result, demonstrating that selectivity arises as the result of a multi-ion process in this system.…”

Atomistic insight into lipid translocation by a TMEM16 scramblase

“…The procedure borrows heavily from the method described in ref. 32. Briefly, we started by fitting a straight line through the groove, assigned 20 equally spaced beads along this string, and minimized the pathway by a simulated annealing procedure.…”

Potassium channels in the heart: structure, function and regulation

“…The existence of K V channels was first inferred over 60 years ago through a combination of functional and theoretical studies in the squid giant axon (Hodgkin & Huxley, 1952). Many of the principles underlying how these channels sense change in membrane voltage and then transduce that into the opening and closing of the voltage-dependent gates are now well established, but there is still a way to go before we will understand voltage sensing and voltage sensor to pore coupling at the same atomic level resolution that we understand the basis of ion selectivity (Zhou et al 2001;Medovoy et al 2016).…”