Abstract
PURPOSE: Neutral small hydrophiles are permeable to varying degrees, across the aqueous pores of phospholipid bilayer protein channels, with their potential for permeation into cells being predictable, on the basis of hydrophilicity and size. Here, it is hypothesized that permeation thresholds for small hydrophiles, across capillary zona occludens tight junction and inter-epithelial junction pore complexes are predictable, on the basis of predicted hydrophilicity in context of predicted molecular size and charge distribution, as are those of cations and anions, on the basis of predicted ionization in context of predicted atomic size. METHODS: Small hydrophiles are categorized by charge distribution. 2-dimensional plots of predicted hydrophilic octanol-to-water partition coefficient (HOWPC; unitless) and predicted van der Waals diameter (vdWD; nm) are generated for each category. The predicted HOWPC-to-vdWD ratio (nm (-1) ), and vdWDs for permeable hydrophile at the maximum and minimum HOWPC-to-vdWD, vdWD @ MAXimum HOWPC-to-vdWD and vdWD @ MINimum HOWPC-to-vdWD are determined. For cations and anions, the ionization-to-atomic diameter ratios (CI or AI-to-AD ratios; nm(-1)) are determined. RESULTS: Per sizes of mixed and pure polyneutral hydrophiles, the permeation size maximum for hydrophiles across tight junction pore complexes is >0.69 ≤ 0.73 nanometers and across inter-epithelial junction pore complexes is ≥ 0.81 nanometers. For hydrophiles with anionicity or cationicity, the vdWDs @ MAXimum HOWPC-to-vdWD are less than those of mixed and polyneutral hydrophiles across both tight and inter-epithelial junctions, ranges specific to category and junction type. For cations, the permeation threshold across tight junctions is between the CI-to-AD ratio of Na+ (+2.69 nm(-1)) and CH3-Hg+ (+2.36 nm(-1)), with CH3-Hg+ and K+ (+2.20 nm(-1)) being permeable; and for divalent cations, the threshold across inter-epithelial junctions is between the CI-to-AD ratio of Mg2+ (+6.25 nm(-1)) and Ca2+ (+5.08 nm(-1)) , Ca2+ being semi-permeable. For anions, the permeation threshold across tight junctions is between the AI-to-AD ratio of Cl- (-4.91 nm(-1)) and Br- (-4.17 nm(-1)), and the threshold across inter-epithelial junctions is between the AI-to-AD ratio of F- (-7.81 nm(-1)) and Cl- (-4.91 nm(-1)). CONCLUSIONS: In silico modeling reveals that permeation thresholds, of small molecule hydrophiles, cations and anions across junctional pore complexes, are conserved in the physiologic state.