Insights on the effect of extracellular acidification on an HCN channel: A molecular dynamics study

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.