Electric Field Induced Wetting of a Hydrophobic Gate in a Model Nanopore Based on the 5-HT<sub>3</sub>Receptor Channel

Klesse, Gianni; Tucker, Stephen J.; Sansom, Mark S. P.

doi:10.1021/acsnano.0c04387

Cited by 32 publications

(45 citation statements)

References 86 publications

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“… 67 In these systems, the presence of a strong (e.g., greater than physiological) electric field corresponding to a transmembrane voltage difference of Δ V = 0.5–1 V drove hydration of an otherwise dewetted hydrophobic gate. The 5-HT 3 R M2 5 system has been employed as a biologically realistic model nanopore 68 which enables detailed exploration of this behavior, including the sensitivity to the water model employed ( Figure 6 ). It can be seen that complete wetting/hydration of the closed state (PDB id 4PIR; see above and Figures 3 and 4 ) requires a field strength in excess of 100 mV/nm (corresponding in this system to a transmembrane voltage difference of Δ V = 0.85 V) when the TIP3P water model is used.…”

Section: Computational Physical Chemistry Of Hydrophobic Gating In Plmentioning

confidence: 99%

“…The data shown in parts B and C are based on simulations of the M2 helix nanopore using the mTIP3P water model. Figure modified with permission from ref ( 68 ). Copyright 2020 American Chemical Society.…”

Section: Computational Physical Chemistry Of Hydrophobic Gating In Plmentioning

confidence: 99%

“…(D, E) Complete channel protein (D) compared with a model nanopore (E) corresponding to the M2 5 pore-lining helix bundle, both illustrated for the 5-HT 3 receptor, with the lipid bilayer in gray/brown. Figures reproduced with permission from ref ( 68 ). Copyright 2020 American Chemical Society.…”

Section: Introduction: Ion Channels and Hydrophobic Gatingmentioning

confidence: 99%

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Molecular Simulations of Hydrophobic Gating of Pentameric Ligand Gated Ion Channels: Insights into Water and Ions

et al. 2021

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Ion channels are proteins which form gated nanopores in biological membranes. Many channels exhibit hydrophobic gating, whereby functional closure of a pore occurs by local dewetting. The pentameric ligand gated ion channels (pLGICs) provide a biologically important example of hydrophobic gating. Molecular simulation studies comparing additive vs polarizable models indicate predictions of hydrophobic gating are robust to the model employed. However, polarizable models suggest favorable interactions of hydrophobic pore-lining regions with chloride ions, of relevance to both synthetic carriers and channel proteins. Electrowetting of a closed pLGIC hydrophobic gate requires too high a voltage to occur physiologically but may inform designs for switchable nanopores. Global analysis of ∼200 channels yields a simple heuristic for structure-based prediction of (closed) hydrophobic gates. Simulation-based analysis is shown to provide an aid to interpretation of functional states of new channel structures. These studies indicate the importance of understanding the behavior of water and ions within the nanoconfined environment presented by ion channels.

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Section: Computational Physical Chemistry Of Hydrophobic Gating In Plmentioning

confidence: 99%

Section: Computational Physical Chemistry Of Hydrophobic Gating In Plmentioning

confidence: 99%

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Molecular Simulations of Hydrophobic Gating of Pentameric Ligand Gated Ion Channels: Insights into Water and Ions

et al. 2021

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“…Electric-field-induced permeation of water and ions was observed in simulations of hydrophobic nanopores [65]; more recently, wetting of hydrophobic gates was demonstrated in simulations of biological ion channels in the presence of a strong electric field [35,66,67]. It has been suggested that the presence of an electric field can alter the liquid-vapour equilibrium of water inside hydrophobic gate, resulting in an increased probability of wetting [66]. This effect might have contributed to water and ion permeation in our simulations.…”

Section: A Hydrophobic Gate With Unusual Featuresmentioning

confidence: 99%

Molecular Dynamics Study of Cl- Permeation through Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)

Zeng

Linsdell

Pomès

2021

Preprint

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The recent elucidation of atomistic structures of Cl - channel CFTR provides opportunities for understanding the molecular basis of cystic fibrosis. Despite having been activated through phosphorylation and provided with ATP ligands, several near-atomistic cryo-EM structures of CFTR are in a closed state, as inferred from the lack of a continuous passage through a hydrophobic bottleneck region located in the extracellular portion of the pore. Here, we present repeated, microsecond-long molecular dynamics simulations of human CFTR solvated in a lipid bilayer and aqueous NaCl. At equilibrium, Cl - ions enter the channel through a lateral intracellular portal and bind to two distinct cationic sites inside the channel pore but do not traverse the narrow, de-wetted bottleneck. Simulations conducted in the presence of a strong hyperpolarizing electric field led to spontaneous chloride translocation events through the bottleneck region of the channel, suggesting that the protein relaxed to a functionally open state. Conformational changes of small magnitude involving transmembrane helices 1 and 6 preceded ion permeation through diverging exit routes at the extracellular end of the pore. Although permeating Cl - ions remain mostly hydrated, partial dehydration occurs at the binding sites and in the bottleneck. This portion of the pore undergoes wetting prior to Cl - translocation, suggesting that it acts as a hydrophobic gate. The observed Cl - pathway is largely consistent with the loci of mutations that alter channel conductance, anion binding, and ion selectivity, supporting the model of the open state of CFTR obtained in the present study.

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“…The behaviour of a hydrophobic gate has been shown to depend critically on the radius of the pore and on the hydrophobicity of the pore lining [16][17][18][19] . Furthermore, in addition to these two structural parameters, the application of an electric field [20][21] or pressure [22][23] can also cause the pore to wet, thereby opening an otherwise closed channel to the passage of water and ions.…”

Section: Introductionmentioning

confidence: 99%

Water Nanoconfined in a Hydrophobic Pore: MD Simulations and Water Models

Lynch

Klesse

Rao

et al. 2021

Preprint

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Water molecules within biological ion channels are in a nano-confined environment and therefore exhibit novel behaviours which differ from that of bulk water. Here, we investigate the phenomenon of hydrophobic gating, the process by which a nanopore may spontaneously de-wet to form a vapour lock if the pore is sufficiently hydrophobic and/or narrow. Notably, this occurs without steric occlusion of the pore. Using molecular dynamics simulations with both additive and polarisable (AMOEBA) force fields, we investigate this wetting/de-wetting behaviour in the TMEM175 ion channel. We examine how a range of rigid fixed-charge (i.e. additive) and polarisable water models affect wetting/de-wetting in both the wild-type structure and in mutants chosen to cover a range of nanopore radii and pore-lining hydrophobicities. Crucially, we find that the rigid fixed-charge water models lead to similar wetting/de-wetting behaviours, but that the polarisable water model resulted in an increased wettability of the hydrophobic gating region of the pore. This has significant implications for molecular simulations of nano-confined water, as it implies that polarisability may need to be included if we are to gain detailed mechanistic insights into wetting/de-wetting processes. These findings are of importance for the design of functionalised biomimetic nanopores (for e.g. sensing or desalination), as well as for furthering our understanding of the mechanistic processes underlying biological ion channel function.

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Electric Field Induced Wetting of a Hydrophobic Gate in a Model Nanopore Based on the 5-HT₃Receptor Channel

Cited by 32 publications

References 86 publications

Molecular Simulations of Hydrophobic Gating of Pentameric Ligand Gated Ion Channels: Insights into Water and Ions

Molecular Simulations of Hydrophobic Gating of Pentameric Ligand Gated Ion Channels: Insights into Water and Ions

Molecular Dynamics Study of Cl- Permeation through Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)

Water Nanoconfined in a Hydrophobic Pore: MD Simulations and Water Models

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Electric Field Induced Wetting of a Hydrophobic Gate in a Model Nanopore Based on the 5-HT3Receptor Channel

Cited by 32 publications

References 86 publications

Molecular Simulations of Hydrophobic Gating of Pentameric Ligand Gated Ion Channels: Insights into Water and Ions

Molecular Simulations of Hydrophobic Gating of Pentameric Ligand Gated Ion Channels: Insights into Water and Ions

Molecular Dynamics Study of Cl- Permeation through Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)

Water Nanoconfined in a Hydrophobic Pore: MD Simulations and Water Models

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Electric Field Induced Wetting of a Hydrophobic Gate in a Model Nanopore Based on the 5-HT₃Receptor Channel