From Gas Phase to Protein Confinement: Characterizing the Conformational Landscape of 1‐Octen‐3‐ol in Bovine Odorant‐Binding Protein

Through their large highly hydrophobic binding pockets, odorant‐binding proteins (OBPs) provide ideal confined environments that can be leveraged to study the conformational ensembles of small volatile molecules under different conditions. To investigate how the conformational landscape of odorants changes between the gas and the condensed phase, we analyzed 1‐octen‐3‐ol (OCT) and bovine OBP (bOBP). Quantum chemical (QC) calculations are combined with high‐resolution microwave spectroscopy to sample the conformational landscape of OCT. To characterize the conformational ensembles of OCT sampled in the gas, water, and protein environment, full atomistic molecular dynamics simulations are carried out. As a supporting parameterization step, different partial charge models are benchmarked for OCT, identifying the ATB webserver as the most consistent option with the reference QC energy landscape. Contrary to previous observations of carvone bound to pOBP, the aqueous environment exhibits a conformational space that matches the gas and protein environment, indicating the presence of lower barriers to interconversion between OCT conformers in the condensed phase. Additionally, the experimentally validated gas‐phase conformer matches the reported structure of OCT in complex with bOBP co‐crystallized in the PDB. Together with the experimental data, the simulations provide a general framework for identifying conformational sub‐spaces of volatile organic compounds in confined environments.