However, as discussed before, there are many situations that justify the use of larger probes because the protein interacts with larger objects, e.g., membrane lipid rafts, cytoskeleton proteins, amyloid plaques, biomaterials surface, biomedical micro-devices and chromatographic media. Also, from the methodology point of view, the probing of the molecular surfaces with at different geometrical resolutions, i.e., using different probe radii, can reveal structural features of the proteins, e.g., shielding of the hydrophobic core. To this end, the present study proposes a methodology for the derivation of atomic hydrophobicity from any hydrophobicity scale, runs a sensitivity analysis to assess the suitability of alternative atom types, and compares the results obtained with atom- and amino acid-level representation of hydrophobicity on molecular surfaces. One of the primary functions of intracellular Ca2+ signaling in polarized epithelia is the regulation of fluid and electrolyte secretion. Ca2+ signals in these cells are organized as polarized Ca2+ waves that are initiated apically due to local clustering of the inositol 1,4,5-trisphosphate receptor Ca2+ release channel. This apical targeting of InsP3Rs creates a “trigger zone” that allows local increases in Ca2+ concentration, which are important for exocytosis, the insertion of key membrane transporters into the apical membrane and their function, which together drive the secretory activity of these cells. There are three isoforms of the InsP3Rs, namely I, II and III. Some polarized epithelial cells, including hepatocytes and bile duct cells, have one principal isoform tethered to the apical membrane while others, such as pancreatic acinar cells, have more than one. In either case, loss of apical InsP3R expression, whether due to decreased InsP3R expression or redistribution away from the apical region, leads to impaired Ca2+ signaling and consequently impaired secretion. Moreover InsP3R deficiency is a common feature in patients with different types of secretory diseases. Despite the importance for cell function, the exact mechanism that tethers InsP3Rs to the apical membrane remains to be determined. There is evidence that the apical localization of InsP3Rs and the function of the “trigger zone” depends upon the integrity of detergent-resistant membranes or lipid rafts, suggesting that these structures act as signaling microdomains that ensure the proper targeting of these receptors. However, it is not clear whether tethering DAPT structure proteins are necessary to target InsP3Rs to these domains of the apical membrane. Extended Synaptotagmins, which are homologous to tricalbins in yeast, are recently identified and characterized ER integral membrane proteins that contain a cytosolic synaptotagmin-like mitochondrial lipid binding protein domain, followed by multiple C2 domains. These tethers allow the formation of ERPM contacts through the InsP3 precursor PIP2 and the regulation of cytosolic Ca2+. Here we investigated whether E-Syts participate in the tethering of the InsP3R to the apical membrane in hepatocytes, a model of polarized epithelial cells in which the machinery for calcium signaling and secretion has been carefully defined.