{
  "abstract": "Extracellular acidification can alter the structure and function of ion channels by neutralizing acidic residues exposed to the extracellular space. However, the relationship between protonation states and alterations in the structural dynamics of the channel is difficult to investigate by experiments. Here, we used atomistic simulations and graph-based algorithms to predict the H-bond pattern of the mouse hyperpolarization-activated cyclic nucleotide-gated (HCN2) channel, whose gating is facilitated by extracellular acidification. Our simulations revealed that E212 — a residue exposed to the extracellular space absent in human HCN channels — participates in a complex hydrogen-bond network with the transmembrane domain. These networks are partially disrupted at acidic pH levels, affecting the molecular interactions of the S4 helix in the channel’s voltage-sensing domain. On the basis of our findings, we suggest that hydrogen-bond network alterations under acidic extracellular conditions can affect channel’s gating.",
  "abstract_shown": true,
  "affiliations": [
    "Research Training Group 2416 MultiSenses - MultiScales, RWTH Aachen University, Aachen, Germany.",
    "IAS-5/INM-9, Computational Biomedicine, Forschungszentrum, Jülich, Germany.",
    "Department of Physics, Theoretical Molecular Biophysics Group, Freie Universität Berlin, Berlin, Germany.",
    "Department of Chemosensation, Institute for Biology II, RWTH Aachen University, Aachen, Germany."
  ],
  "article_type": "Research Article",
  "arxiv": null,
  "author_total": 4,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Somayeh Asgharpour",
      "orcid": "0000-0001-7999-4762"
    },
    {
      "affs": [
        2
      ],
      "name": "Michalis Lazaratos"
    },
    {
      "affs": [
        0,
        3
      ],
      "name": "Marc Spehr"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Paolo Carloni",
      "orcid": "0000-0002-9010-0149"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/d7qk8mcvtsfaj.bib",
  "cited_by": 0,
  "doi": "10.1371/journal.pone.0360058",
  "fulltext_url": "https://europepmc.org/articles/PMC13704849",
  "id": "d7qk8mcvtsfaj",
  "issns": [
    "1932-6203"
  ],
  "landing_url": "https://doi.org/10.1371/journal.pone.0360058",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|Ion channel regulation and function"
    ],
    [
      "plos",
      "/Biology and life sciences/Biochemistry/Proteins/Ion channels/Cyclic nucleotide-gated channels/Hyperpolarization-activated cyclic nucleotide-gated channels"
    ],
    [
      "plos",
      "/Biology and life sciences/Biochemistry/Proteins/Ion channels/Ion channel gating"
    ],
    [
      "plos",
      "/Biology and life sciences/Biochemistry/Proteins/Ion channels/Potassium channels"
    ],
    [
      "plos",
      "/Biology and life sciences/Biochemistry/Proteins/Ion channels/Proton channels/Voltage-gated proton channels"
    ],
    [
      "plos",
      "/Biology and life sciences/Biochemistry/Proteins/Ion channels/Sodium channels/Voltage-gated sodium channels"
    ],
    [
      "plos",
      "/Biology and life sciences/Biochemistry/Proteins/Ion channels/Voltage-gated ion channels"
    ],
    [
      "plos",
      "/Biology and life sciences/Biochemistry/Proteins/Ion channels/Voltage-gated ion channels/Hyperpolarization-activated cyclic nucleotide-gated channels"
    ],
    [
      "plos",
      "/Biology and life sciences/Biochemistry/Proteins/Ion channels/Voltage-gated ion channels/Voltage-gated proton channels"
    ],
    [
      "plos",
      "/Biology and life sciences/Biochemistry/Proteins/Ion channels/Voltage-gated ion channels/Voltage-gated sodium channels"
    ],
    [
      "plos",
      "/Biology and life sciences/Biochemistry/Salt bridges"
    ],
    [
      "plos",
      "/Biology and life sciences/Biophysics/Ion channels/Cyclic nucleotide-gated channels/Hyperpolarization-activated cyclic nucleotide-gated channels"
    ],
    [
      "plos",
      "/Biology and life sciences/Biophysics/Ion channels/Ion channel gating"
    ],
    [
      "plos",
      "/Biology and life sciences/Biophysics/Ion channels/Potassium channels"
    ],
    [
      "plos",
      "/Biology and life sciences/Biophysics/Ion channels/Proton channels/Voltage-gated proton channels"
    ],
    [
      "plos",
      "/Biology and life sciences/Biophysics/Ion channels/Sodium channels/Voltage-gated sodium channels"
    ],
    [
      "plos",
      "/Biology and life sciences/Biophysics/Ion channels/Voltage-gated ion channels"
    ],
    [
      "plos",
      "/Biology and life sciences/Biophysics/Ion channels/Voltage-gated ion channels/Hyperpolarization-activated cyclic nucleotide-gated channels"
    ],
    [
      "plos",
      "/Biology and life sciences/Biophysics/Ion channels/Voltage-gated ion channels/Voltage-gated proton channels"
    ],
    [
      "plos",
      "/Biology and life sciences/Biophysics/Ion channels/Voltage-gated ion channels/Voltage-gated sodium channels"
    ],
    [
      "plos",
      "/Biology and life sciences/Cell biology/Extracellular space"
    ],
    [
      "plos",
      "/Biology and life sciences/Neuroscience/Neurophysiology/Ion channels/Cyclic nucleotide-gated channels/Hyperpolarization-activated cyclic nucleotide-gated channels"
    ],
    [
      "plos",
      "/Biology and life sciences/Neuroscience/Neurophysiology/Ion channels/Ion channel gating"
    ],
    [
      "plos",
      "/Biology and life sciences/Neuroscience/Neurophysiology/Ion channels/Potassium channels"
    ],
    [
      "plos",
      "/Biology and life sciences/Neuroscience/Neurophysiology/Ion channels/Proton channels/Voltage-gated proton channels"
    ],
    [
      "plos",
      "/Biology and life sciences/Neuroscience/Neurophysiology/Ion channels/Sodium channels/Voltage-gated sodium channels"
    ],
    [
      "plos",
      "/Biology and life sciences/Neuroscience/Neurophysiology/Ion channels/Voltage-gated ion channels"
    ],
    [
      "plos",
      "/Biology and life sciences/Neuroscience/Neurophysiology/Ion channels/Voltage-gated ion channels/Hyperpolarization-activated cyclic nucleotide-gated channels"
    ],
    [
      "plos",
      "/Biology and life sciences/Neuroscience/Neurophysiology/Ion channels/Voltage-gated ion channels/Voltage-gated proton channels"
    ],
    [
      "plos",
      "/Biology and life sciences/Neuroscience/Neurophysiology/Ion channels/Voltage-gated ion channels/Voltage-gated sodium channels"
    ],
    [
      "plos",
      "/Biology and life sciences/Physiology/Electrophysiology/Ion channels/Cyclic nucleotide-gated channels/Hyperpolarization-activated cyclic nucleotide-gated channels"
    ],
    [
      "plos",
      "/Biology and life sciences/Physiology/Electrophysiology/Ion channels/Ion channel gating"
    ],
    [
      "plos",
      "/Biology and life sciences/Physiology/Electrophysiology/Ion channels/Potassium channels"
    ],
    [
      "plos",
      "/Biology and life sciences/Physiology/Electrophysiology/Ion channels/Proton channels/Voltage-gated proton channels"
    ],
    [
      "plos",
      "/Biology and life sciences/Physiology/Electrophysiology/Ion channels/Sodium channels/Voltage-gated sodium channels"
    ],
    [
      "plos",
      "/Biology and life sciences/Physiology/Electrophysiology/Ion channels/Voltage-gated ion channels"
    ],
    [
      "plos",
      "/Biology and life sciences/Physiology/Electrophysiology/Ion channels/Voltage-gated ion channels/Hyperpolarization-activated cyclic nucleotide-gated channels"
    ],
    [
      "plos",
      "/Biology and life sciences/Physiology/Electrophysiology/Ion channels/Voltage-gated ion channels/Voltage-gated proton channels"
    ],
    [
      "plos",
      "/Biology and life sciences/Physiology/Electrophysiology/Ion channels/Voltage-gated ion channels/Voltage-gated sodium channels"
    ],
    [
      "plos",
      "/Biology and life sciences/Physiology/Electrophysiology/Neurophysiology/Ion channels/Cyclic nucleotide-gated channels/Hyperpolarization-activated cyclic nucleotide-gated channels"
    ],
    [
      "plos",
      "/Biology and life sciences/Physiology/Electrophysiology/Neurophysiology/Ion channels/Ion channel gating"
    ],
    [
      "plos",
      "/Biology and life sciences/Physiology/Electrophysiology/Neurophysiology/Ion channels/Potassium channels"
    ],
    [
      "plos",
      "/Biology and life sciences/Physiology/Electrophysiology/Neurophysiology/Ion channels/Proton channels/Voltage-gated proton channels"
    ],
    [
      "plos",
      "/Biology and life sciences/Physiology/Electrophysiology/Neurophysiology/Ion channels/Sodium channels/Voltage-gated sodium channels"
    ],
    [
      "plos",
      "/Biology and life sciences/Physiology/Electrophysiology/Neurophysiology/Ion channels/Voltage-gated ion channels"
    ],
    [
      "plos",
      "/Biology and life sciences/Physiology/Electrophysiology/Neurophysiology/Ion channels/Voltage-gated ion channels/Hyperpolarization-activated cyclic nucleotide-gated channels"
    ],
    [
      "plos",
      "/Biology and life sciences/Physiology/Electrophysiology/Neurophysiology/Ion channels/Voltage-gated ion channels/Voltage-gated proton channels"
    ],
    [
      "plos",
      "/Biology and life sciences/Physiology/Electrophysiology/Neurophysiology/Ion channels/Voltage-gated ion channels/Voltage-gated sodium channels"
    ],
    [
      "plos",
      "/Physical sciences/Chemistry/Electrochemistry/Salt bridges"
    ],
    [
      "plos",
      "/Physical sciences/Physics/Biophysics/Ion channels/Cyclic nucleotide-gated channels/Hyperpolarization-activated cyclic nucleotide-gated channels"
    ],
    [
      "plos",
      "/Physical sciences/Physics/Biophysics/Ion channels/Ion channel gating"
    ],
    [
      "plos",
      "/Physical sciences/Physics/Biophysics/Ion channels/Potassium channels"
    ],
    [
      "plos",
      "/Physical sciences/Physics/Biophysics/Ion channels/Proton channels/Voltage-gated proton channels"
    ],
    [
      "plos",
      "/Physical sciences/Physics/Biophysics/Ion channels/Sodium channels/Voltage-gated sodium channels"
    ],
    [
      "plos",
      "/Physical sciences/Physics/Biophysics/Ion channels/Voltage-gated ion channels"
    ],
    [
      "plos",
      "/Physical sciences/Physics/Biophysics/Ion channels/Voltage-gated ion channels/Hyperpolarization-activated cyclic nucleotide-gated channels"
    ],
    [
      "plos",
      "/Physical sciences/Physics/Biophysics/Ion channels/Voltage-gated ion channels/Voltage-gated proton channels"
    ],
    [
      "plos",
      "/Physical sciences/Physics/Biophysics/Ion channels/Voltage-gated ion channels/Voltage-gated sodium channels"
    ]
  ],
  "openalex": "W7223669448",
  "pdf_url": "https://europepmc.org/articles/PMC13704849?pdf=render",
  "pmcid": "PMC13704849",
  "pmid": "42932303",
  "published": "2026-10-26",
  "publisher": "Public Library of Science",
  "ris": "https://research.draconitic.com/paper/d7qk8mcvtsfaj.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:17Z",
      "native_id": "10.1371/journal.pone.0360058",
      "source": "plos",
      "url": "https://doi.org/10.1371/journal.pone.0360058"
    },
    {
      "first_seen": "2026-10-30T12:22:01Z",
      "native_id": "MED:42932303",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42932303"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "plos:biophysics",
      "subfield": "biophysics"
    },
    {
      "field": "biology",
      "origin": "plos:neuroscience",
      "subfield": "neuroscience"
    },
    {
      "field": "medicine",
      "origin": "plos:physiology",
      "subfield": "physiology"
    }
  ],
  "title": "Insights on the effect of extracellular acidification on an HCN channel: A molecular dynamics study",
  "title_text": "Insights on the effect of extracellular acidification on an HCN channel: A molecular dynamics study",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:22:01Z",
  "url": "https://research.draconitic.com/paper/d7qk8mcvtsfaj",
  "venue": "PLOS One",
  "versions": []
}