Hydrophobicity profiles in G protein-coupled receptor transmembrane helical domains.

Abstract

The lack of a crystallographically derived structure for all but three G (TP [guanosine triphosphate]-binding) protein-coupled receptor (GPCRs) proteins necessitates the use of computationally derived methods to determine their structures. Computational methodologies allow a mechanistic glimpse into GPCR-ligand interactions at a molecular level to better understand the initial steps leading to a protein's biologic functions, ie, protecting the ligands that activate, deactivate, or inhibit the protein, stabilizing protein structure in the membrane's lipid bilayer, and ensuring that the hydrophilic environment within the GPCR-binding pocket is maintained. Described here is a formalism that quantifies the amphiphilic nature of a helix, by determining the effective hydrophobicity (or hydrophilicity) at specific positions around it. This formalism will enable computational protein modelers to position helices so that the functional aspects of GPCRs are adequately represented in the model. Hydro-Eff®, an online tool, allows users to calculate effective helical hydrophobicities.