Lipid-mediated hydrophobic gating in the BK potassium channel
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arXiv
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| Format: | Preprint |
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2024
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| _version_ | 1866929337570164736 |
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| author | Coronel, Lucia Di Muccio, Giovanni Rothberg, Brad Giacomello, Alberto Carnevale, Vincenzo |
| author_facet | Coronel, Lucia Di Muccio, Giovanni Rothberg, Brad Giacomello, Alberto Carnevale, Vincenzo |
| contents | The large-conductance, calcium-activated potassium (BK) channel lacks the typical intracellular bundle-crossing gate present in most ion channels of the 6TM family. This observation, initially inferred from Ca$^{2+}$-free-pore accessibility experiments and recently corroborated by a CryoEM structure of the non-conductive state, raises a puzzling question: how can gating occur in absence of steric hindrance? To answer this question, we carried out molecular simulations and accurate free energy calculations to obtain a microscopic picture of the sequence of events that, starting from a Ca$^{2+}$-free state leads to ion conduction upon Ca$^{2+}$ binding. Our results highlight an unexpected role for annular lipids, which turn out to be an integral part of the gating machinery. Due to the presence of fenestrations, the "closed" Ca$^{2+}$-free pore can be occupied by the methyl groups from the lipid alkyl chains. This dynamic occupancy triggers and stabilizes the nucleation of a vapor bubble into the inner pore cavity, thus hindering ion conduction. By contrast, Ca$^{2+}$ binding results into a displacement of these lipids outside the inner cavity, lowering the hydrophobicity of this region and thus allowing for pore hydration and conduction. This lipid-mediated hydrophobic gating rationalizes several seemingly problematic experimental observations, including the state-dependent pore accessibility of blockers. |
| format | Preprint |
| id |
arxiv_https___arxiv_org_abs_2405_04644 |
| institution | arXiv |
| publishDate | 2024 |
| record_format | arxiv |
| spellingShingle | Lipid-mediated hydrophobic gating in the BK potassium channel Coronel, Lucia Di Muccio, Giovanni Rothberg, Brad Giacomello, Alberto Carnevale, Vincenzo Biomolecules Biological Physics Chemical Physics The large-conductance, calcium-activated potassium (BK) channel lacks the typical intracellular bundle-crossing gate present in most ion channels of the 6TM family. This observation, initially inferred from Ca$^{2+}$-free-pore accessibility experiments and recently corroborated by a CryoEM structure of the non-conductive state, raises a puzzling question: how can gating occur in absence of steric hindrance? To answer this question, we carried out molecular simulations and accurate free energy calculations to obtain a microscopic picture of the sequence of events that, starting from a Ca$^{2+}$-free state leads to ion conduction upon Ca$^{2+}$ binding. Our results highlight an unexpected role for annular lipids, which turn out to be an integral part of the gating machinery. Due to the presence of fenestrations, the "closed" Ca$^{2+}$-free pore can be occupied by the methyl groups from the lipid alkyl chains. This dynamic occupancy triggers and stabilizes the nucleation of a vapor bubble into the inner pore cavity, thus hindering ion conduction. By contrast, Ca$^{2+}$ binding results into a displacement of these lipids outside the inner cavity, lowering the hydrophobicity of this region and thus allowing for pore hydration and conduction. This lipid-mediated hydrophobic gating rationalizes several seemingly problematic experimental observations, including the state-dependent pore accessibility of blockers. |
| title | Lipid-mediated hydrophobic gating in the BK potassium channel |
| topic | Biomolecules Biological Physics Chemical Physics |
| url | https://arxiv.org/abs/2405.04644 |