Ion-triggered selectivity in bacterial sodium channels

Abstract

Since the availability of the first crystal structure of a bacterial Na channel in 2011, understanding selectivity across this family of membrane proteins has been the subject of intense research efforts. Initially, free energy calculations based on molecular dynamics simulations revealed that although sodium ions can easily permeate the channel with their first hydration shell almost intact, the selectivity filter is too narrow for efficient conduction of hydrated potassium ions. This steric view of selectivity was subsequently questioned by microsecond atomic trajectories, which proved that the selectivity filter appears to the permeating ions as a highly degenerate, liquid-like environment. Although this liquid-like environment looks optimal for rapid conduction of Na, it seems incompatible with efficient discrimination between similar ion species, such as Na and K, through steric effects. Here extensive molecular dynamics simulations, combined with Markov state model analyses, reveal that at positive membrane potentials, potassium ions trigger a conformational change of the selectivity toward a nonconductive metastable state. It is this transition of the selectivity filter, and not steric effects, that prevents the outward flux of K at positive membrane potentials. This description of selectivity, triggered by the nature of the permeating ions, might have implications on the current understanding of how ion channels, and in particular bacterial Na channels, operate at the atomic scale.

Selectivity filter modalities and rapid inactivation of the hERG1 channel

“…In contrast to WT, the filter of hERG1-N629D can permeate Na + and displays sensitivity to the settings used in our simulations. Similar properties have been reported for bacterial sodium channels, for which the EEEE ring at the filter induces sensitivity to a myriad of conditions like cation type, cation configuration, concentration gradients, and applied voltage in simulations (49). Therefore, the sensitivity of SF dynamics to initial conditions observed in hERG1-N629D simulations could be a consequence of the ring of negative charges (DDDD) at the outer-mouth vestibule of the mutant filter.…”

“…A clear gap between the first and the second relaxation times (SI Appendix, Fig. S7C) suggested that two-state hidden Markov model (HMM) can be used to sufficiently describe states from the selected MD trajectories (48,49). The resulting metastable states (Fig.…”

Bases of Bacterial Sodium Channel Selectivity Among Organic Cations

“…The analysis of the equilibrium MD simulations performed shows that ~11 and 6% of all data display inward-facing (dunked) conformation for WT and E/D SF, respectively. This finding is in good accord with previous studies performed at equilibrium and different biasing conditions 23,24 . The distribution of states, however, appears to show strong dependence on the polarity of membrane potential as well as the specific force-field used 19,23,24 .…”

“…Transitions between different doubly-occupied states were seldom found, and most of the transitions observed required single-ion occupancy in the filter 22 . Furini and Domene reported even higher presence of a singly occupied state representing of ~40% of all functional states involved into Na + permeation 24 .…”

“…Furthermore, dynamic and ion-dependent conformational dynamics of acidic residues in the Nav SF (flipping) were proposed to play significant roles in catalyzing selective transport of Na + 22,23 . The combination of multi-microseconds long all-atom MD simulations with Markov-State analysis suggested that the liquid-like dynamical structure of the Nav SF can potentially be modulated by binding of different cations with conformational dynamics of acidic residues on the same time-scales as catalyzed ion movement 24 . This coupling between conformational transition in the selectivity filter and ion movement may also play a significant, yet not fully-understood, role in the well-established differences between inward- and outward-ion transport enabled by Navs 23 .…”