Connexin channels mediate selective diffusive movement of molecules through plasma membrane(s). These channels have a wide pore where ions and small molecules up to 1 kDa can cross freely. One can imagine then that having these channels open is detrimental to the cell. The uniqueness of connexins' gating mechanism and wide pore present exciting challenges and opportunities in the biomolecular simulation field. To gain insight into the physics that underlie selective molecular permeation, we investigated the energetics of two uncharged derivatized sugars, one permeable and one impermeable, through a validated connexin26 (Cx26) channel structural model, using molecular dynamics and free energy calculation. The results suggest that for the tested molecules, differences in hydrogen bonding and entropic factors arising from permeant flexibility substantially contribute to the energetics of permeation. This work highlights factors involved in selective molecular permeation that differ from those that define selectivity among atomic ions. In the meanwhile, we used molecular dynamics simulations to identify the electrostatic network change caused by calcium binding and revealed a general calcium gating mechanism across connexins. More than 100 mutations have been described for the human Cx26 gene, and these alone are responsible for ~50% of childhood non-syndromic recessive hearing loss. We explored how the N14K mutant promotes gain in function and N14Y mutant causes loss of function. We performed ANOVA analysis of pair-wise correlation and pair-wise interaction among multiple copies of Cx26 WT, N14K, and N14Y molecular dynamics trajectories and identified several critical interactions between N-terminal domain and cytoplasmic loop. Our data suggest that disruption of NT-CL interaction facilitates hemichannel opening and stabilizes the open state.

Insights on small molecular permeation and gating functions of Connexin26 hemichannels

256th National Meeting (2018)

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