Structural dynamics of olfactory receptors: implications for odorant binding and activation mechanisms

Olfaction, an ancient and intricate process, profoundly shapes human innate responses yet remains relatively understudied compared to other sensory modalities. Olfactory receptors (ORs), members of the G protein-coupled receptor (GPCR) family, play a pivotal role in detecting and discriminating a vast array of odorants. This comprehensive study explores the functional roles of five diverse ORs: OR1A1, OR2W1, OR11A1, OR51E1 and OR51E2, through detailed investigations into the differences between their apo and odorant-bound forms. By examining key residues and mutations, the possible molecular mechanisms that underlie the modulation of binding landscapes and the consequent alterations in OR stability were elucidated. The findings revealed dynamic conformational changes in ORs upon odorant binding, characterized by hinging motions and tilting of transmembrane helices. Using residue interaction network analyses, critical residues involved in mediating interactions between ORs and odorants were uncovered, shedding light on the molecular determinants of olfactory perception. By examining changes in binding pocket volume and per-residue energy decomposition, the dynamic nature of OR activation and the influence of mutations on receptor stability and functionality was observed.