Abstract
In this paper, a combined statistical physics and computational modeling framework was used to elucidate the molecular mechanism of olfaction through a putative adsorption process in which coumarin compounds bind to the mouse olfactory receptors Olfr924, Olfr285, and Olfr1016. Adsorption isotherms derived from experimental data were analyzed using both monolayer and double-layer statistical physics models, enabling the quantitative determination of steric and energetic parameters governing odorant-receptor interactions. The steric analysis reveals diverse anchoring behaviors, with coumarin molecules adopting both parallel and non-parallel orientations relative to receptor binding sites, indicative of mixed adsorption configurations. The estimated adsorption energies, ranging from 13.563 to 33.872 kJ/mol, suggest that the coumarin compounds are physically adsorbed onto the receptors, offering insight into the steric and energetic heterogeneity of the receptor. Moreover, the application of statistical physics modeling enabled a detailed steric characterization of the receptor surface through binding site size distributions (BSDs) and an energetic characterization via adsorption energy distributions (AEDs). To complement microscopic analysis, a macroscopic thermodynamic study was also performed, providing further insight into the adsorption behavior of coumarin compounds on the olfactory receptors. To further validate and complement these findings, molecular docking simulations were performed to identify interaction types and binding modes between coumarin ligands and olfactory receptors. Together, these results demonstrate the effectiveness of integrating statistical physics modeling with molecular docking to elucidate mechanisms of olfactory perception at both microscopic and macroscopic scales. The three complexes formed between coumarin and the olfactory receptor sites (Olfr285, Olfr924, and Olfr1016) have been analyzed using molecular docking simulations, molecular dynamics simulations, and free binding energies calculated using the molecular mechanics-Poisson-Boltzmann surface (MM-PBSA) and molecular mechanics-generalized Born surface (MM-GBSA) methods.