Brownian Permeability Computation Model Predicts That Differences in the Internal Radii of the Pore are Determinant for Unidirectional and Reversal Fluxes through Gap Junction Channels

Abstract

Gap junctions are vital in multiple organs’ physiology and are linked to severe genetic diseases. Connexins are the proteins forming these gap junction channels which allow molecular and ionic selective-diffusion amongst neighboring cells. Selectivity is connexin-type dependent. In between HeLa cells expressing distinct connexins (e.g. Cx43 and Cx45), heterotypic channels formed induce a preferential flux of large fluorescent molecules towards the Cx43 side. The independence to molecule's charge, points towards a high relevance of the channel's pore shape. To study the effects of pore shape on particles movement, a 3D-computational channel model was developed, emulating X-ray crystallographic structures from Cx43 and Cx26. The sections of the pore were approximated to standard geometric shapes including a central ellipsoidal vestibule. Ellipsoids were placed on either ends of the pore, representing controlled volumes from coupled cells. Particles were modeled as spheres and Brownian dynamics was used to model particles’ interactions. Simulations for different pore geometries show that against conventional thought, some shapes can explain the direction of the preferential flux data that comply with the electrical resistances measured through electrophysiological recordings. This pore-geometry causes a different intra-pore mechanism that requires an asymmetric vestibule with radii comparable to the particle size. In our simulations when particles were introduced from the side of the pore where the inner mouth is larger, particles reside longer in the vestibule using it as an intermediate stop and forcing the particles to cross faster to the other side of the pore.