Figure 5. Schematic ion channel with... | Rockefeller University Press

Figure 5.

Schematic ion channel with potential sites for drug modulation of function and the associated contributions toΔGtotalI→II. 1, binding in the pore (active site) to block ion movement, which may be small, maybe zero; 2, binding to allosteric sites formed by the protein, which will contribute to ΔGproteinI→II (e.g., Jackson, 1989); 3, binding to allosteric sites formed by the protein plus bilayer lipids, which will contribute both ΔGproteinI→II and ΔGbilayerI→II (e.g., Obi and Natesan, 2022), as well as the so-called residual exposure contribution ΔGresI→II due to imperfects hydrophobic matching between membrane proteins and their host bilayer (Mondal et al., 2011); 4, non-specific binding/enrichment at the protein/bilayer boundary, which will contribute to ΔGbilayerI→II and maybe also ΔGresI→II; and 5, partitioning into the bilayer/solution interface to alter bulk bilayer properties, which will contribute to ΔGbilayerI→II. After Andersen, 2008 and Herold et al., 2014; see also Urban, 2002.

Schematic ion channel with potential sites for drug modulation of function and the associated contributions to $Δ G_{total}^{I \to II} .$ 1, binding in the pore (active site) to block ion movement, which may be small, maybe zero; 2, binding to allosteric sites formed by the protein, which will contribute to $Δ G_{protein}^{I \to II}$ (e.g., Jackson, 1989); 3, binding to allosteric sites formed by the protein plus bilayer lipids, which will contribute both $Δ G_{protein}^{I \to II}$ and $Δ G_{bilayer}^{I \to II}$ (e.g., Obi and Natesan, 2022), as well as the so-called residual exposure contribution $(Δ G_{res}^{I \to II})$ due to imperfects hydrophobic matching between membrane proteins and their host bilayer (Mondal et al., 2011); 4, non-specific binding/enrichment at the protein/bilayer boundary, which will contribute to $Δ G_{bilayer}^{I \to II}$ and maybe also $Δ G_{res}^{I \to II};$ and 5, partitioning into the bilayer/solution interface to alter bulk bilayer properties, which will contribute to $Δ G_{bilayer}^{I \to II} .$ After Andersen, 2008 and Herold et al., 2014; see also Urban, 2002.