The conduction pathway of potassium channels is water free under physiological conditions

Öster, Carl; Hendriks, Kitty; Kopeć, Wojciech; Chevelkov, Veniamin; Shi, Chaowei; Michl, Dagmar; Lange, Adam; Sun, Han; Groot, Bert L. de; Lange, Adam

doi:10.1126/sciadv.aaw6756

Cited by 57 publications

(71 citation statements)

References 50 publications

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“…For the NaK2K system from our recent publications 29,95 . We used the high-resolution structure of NaK2K (PDB ID: 3OUF 96 ) with F92A mutation 97 , embedded in a POPC membrane.…”

Section: Methodsmentioning

confidence: 99%

Molecular mechanism of a potassium channel gating through activation gate-selectivity filter coupling

2019

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Potassium channels are presumed to have two allosterically coupled gates, the activation gate and the selectivity filter gate, that control channel opening, closing, and inactivation. However, the molecular mechanism of how these gates regulate K+ ion flow through the channel remains poorly understood. An activation process, occurring at the selectivity filter, has been recently proposed for several potassium channels. Here, we use X-ray crystallography and extensive molecular dynamics simulations, to study ion permeation through a potassium channel MthK, for various opening levels of both gates. We find that the channel conductance is controlled at the selectivity filter, whose conformation depends on the activation gate. The crosstalk between the gates is mediated through a collective motion of channel helices, involving hydrophobic contacts between an isoleucine and a conserved threonine in the selectivity filter. We propose a gating model of selectivity filter-activated potassium channels, including pharmacologically relevant two-pore domain (K2P) and big potassium (BK) channels.

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“…For the NaK2K system from our recent publications 29,95 . We used the high-resolution structure of NaK2K (PDB ID: 3OUF 96 ) with F92A mutation 97 , embedded in a POPC membrane.…”

Section: Methodsmentioning

confidence: 99%

Molecular mechanism of a potassium channel gating through activation gate-selectivity filter coupling

2019

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“… 407 Data from two-dimensional infrared spectroscopy experiments have been interpreted as implicating water in the filter, 24 , 25 although this has been contested, 419 and solid-state NMR experiments suggest the conduction pathway in the filter may be water-free. 420 Although details remain to be resolved (see ref ( 411 ) for a measured review), it is clear that there is a complex role of conformational flexibility within the selectivity filter and elsewhere in the KcsA channel, 25 which determines the relative occupancies of the filter by ions or water in its different conformational states. This is consistent with the more general emerging view of biological nanopores (see above) whereby local changes in conformation and/or electrostatics of narrow protein pores can modulate their water permeability.…”

Section: Ion Channelsmentioning

confidence: 99%

Water in Nanopores and Biological Channels: A Molecular Simulation Perspective

2020

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This Review explores the dynamic behavior of water within nanopores and biological channels in lipid bilayer membranes. We focus on molecular simulation studies, alongside selected structural and other experimental investigations. Structures of biological nanopores and channels are reviewed, emphasizing those high-resolution crystal structures, which reveal water molecules within the transmembrane pores, which can be used to aid the interpretation of simulation studies. Different levels of molecular simulations of water within nanopores are described, with a focus on molecular dynamics (MD). In particular, models of water for MD simulations are discussed in detail to provide an evaluation of their use in simulations of water in nanopores. Simulation studies of the behavior of water in idealized models of nanopores have revealed aspects of the organization and dynamics of nanoconfined water, including wetting/dewetting in narrow hydrophobic nanopores. A survey of simulation studies in a range of nonbiological nanopores is presented, including carbon nanotubes, synthetic nanopores, model peptide nanopores, track-etched nanopores in polymer membranes, and hydroxylated and functionalized nanoporous silica. These reveal a complex relationship between pore size/geometry, the nature of the pore lining, and rates of water transport. Wider nanopores with hydrophobic linings favor water flow whereas narrower hydrophobic pores may show dewetting. Simulation studies over the past decade of the behavior of water in a range of biological nanopores are described, including porins and β-barrel protein nanopores, aquaporins and related polar solute pores, and a number of different classes of ion channels. Water is shown to play a key role in proton transport in biological channels and in hydrophobic gating of ion channels. An overall picture emerges, whereby the behavior of water in a nanopore may be predicted as a function of its hydrophobicity and radius. This informs our understanding of the functions of diverse channel structures and will aid the design of novel nanopores. Thus, our current level of understanding allows for the design of a nanopore which promotes wetting over dewetting or vice versa. However, to design a novel nanopore, which enables fast, selective, and gated flow of water de novo would remain challenging, suggesting a need for further detailed simulations alongside experimental evaluation of more complex nanopore systems.

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“…Yet, new ion transport proteins, structures, functions, and mechanisms of both new and old transport proteins are discovered almost daily. This makes the field of ion channels and transporters one of the most active in molecular biology (15,35,41,68,69,70,71,72,73,74,75,76,77,78,79,80).…”

Section: Ions In Protein Binding Sitesmentioning

confidence: 99%

“…Though this solution chemistry experiment would be an exceedingly natural assessment of biomolecular hydration mimicry, it has not been done as far as we know. Answers to such questions, and the natural follow-up questions, would address current issues of H2O occupancy of potassium channels (41,80,134,135).…”

Section: Qct and Protein Binding Sitesmentioning

confidence: 99%

Hydration Mimicry by Membrane Ion Channels

Chaudhari

Vanegas

Pratt

et al. 2020

Annu. Rev. Phys. Chem.

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Ions transiting biomembranes might pass readily from water through ion-specific membrane proteins if those protein channels provide environments similar to the aqueous solution hydration environment. Indeed, bulk aqueous solution is an important reference condition for the ion permeation process. Assessment of this hydration mimicry view depends on understanding the hydration structure and free energies of metal ions in water to provide a comparison for the membrane channel environment. To refine these considerations, we review local hydration structures of ions in bulk water, and the molecular quasi-chemical theory that provides hydration free energies. In that process, we note some current views of ion-binding to membrane channels, and suggest new physical chemical calculations and experiments that might further clarify the hydration mimicry view.

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The conduction pathway of potassium channels is water free under physiological conditions

Cited by 57 publications

References 50 publications

Molecular mechanism of a potassium channel gating through activation gate-selectivity filter coupling

Molecular mechanism of a potassium channel gating through activation gate-selectivity filter coupling

Water in Nanopores and Biological Channels: A Molecular Simulation Perspective

Hydration Mimicry by Membrane Ion Channels

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