Insights on the effect of extracellular acidification on an HCN channel: A molecular dynamics study
4 affiliations
- 1Research Training Group 2416 MultiSenses - MultiScales, RWTH Aachen University, Aachen, Germany.
- 2IAS-5/INM-9, Computational Biomedicine, Forschungszentrum, Jülich, Germany.
- 3Department of Physics, Theoretical Molecular Biophysics Group, Freie Universität Berlin, Berlin, Germany.
- 4Department of Chemosensation, Institute for Biology II, RWTH Aachen University, Aachen, Germany.
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.
Related
- The structural dynamics and molecular coupling in the slow inactivation of a prokaryotic voltage-gated sodium channel
- Structural insights into an aptainhibitor of the SARS-CoV-2 E protein using molecular docking, molecular dynamics, and biophysical analyses
- Co-Titration of Phosphatidylserine Lipids and a Channel Protein Using Constant pH Molecular Dynamics
- Molecular Modeling of Isoniazid Encapsulation by β-Cyclodextrin for Drug Delivery: Molecular Dynamics, Interaction Energies, and DFT Insights
- Sulfate ions promote Cnm-mediated aggregation in Streptococcus mutans: molecular dynamics insights into the oral–systemic connection
BibTeX
@article{asgharpour2026insights,
title = {{Insights on the effect of extracellular acidification on an HCN channel: A molecular dynamics study}},
author = {Somayeh Asgharpour and Michalis Lazaratos and Marc Spehr and Paolo Carloni},
journal = {PLOS One},
year = {2026},
month = oct,
doi = {10.1371/journal.pone.0360058},
url = {https://doi.org/10.1371/journal.pone.0360058},
note = {CC BY},
}
RIS
TY - JOUR
TI - Insights on the effect of extracellular acidification on an HCN channel: A molecular dynamics study
AU - Somayeh Asgharpour
AU - Michalis Lazaratos
AU - Marc Spehr
AU - Paolo Carloni
PY - 2026
DA - 2026/10/26
JO - PLOS One
DO - 10.1371/journal.pone.0360058
UR - https://doi.org/10.1371/journal.pone.0360058
AB - 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.
SN - 1932-6203
ER -