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

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 domain's 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.