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bioRxiv · 10.1101/2025.09.05.674486

Insights on the effect of extracellular acidification on an HCNchannel: a molecular dynamics study

Asgharpour, S.·Lazaratos, M.·Spehr, M.·Carloni, P.
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Abstract

Extracellular acidification may affect the structure and function of ion channels by neutralizing acidic residues exposed to the extracellular space. However, the relationship between these changes in the protonation state and alterations in the channels structure and dynamics remains unclear. Here, we used atomistic simulations and graph-based algorithms to study mice hyperpolarization-activated cyclic nucleotide-gated type 2 channels, whose gating is facilitated by extracellular acidification. Our simulations revealed that E212, a residue facing the extracellular space, may be involved in complex hydrogen bond networks with the S4 helix, which plays a role in the gating mechanism. This network is partially disrupted at acidic pH levels, affecting the molecular interactions of the S4 helix. This, in turn, may alter the domains response to membrane voltage changes and, consequently, gating. We conclude that the H-bond network from an extracellular residue to the main gating domain may be an important factor in the observed channel activities at different pH levels. O_FIG O_LINKSMALLFIG WIDTH=157 HEIGHT=200 SRC="FIGDIR/small/674486v1_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@11a34c6org.highwire.dtl.DTLVardef@17ec631org.highwire.dtl.DTLVardef@5e9e4org.highwire.dtl.DTLVardef@3ea8fc_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Asgharpour, S., Lazaratos, M., Spehr, M., Carloni, P.. 2025-09-07. Insights on the effect of extracellular acidification on an HCNchannel: a molecular dynamics study. https://doi.org/10.1101/2025.09.05.674486

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