Ensemble-Based Descriptor Analysis of Flexible Odorants: Conformational Landscapes of Geraniol, Nerol, and Linalool

Abstract

Abstract Conformational flexibility remains a central challenge in the molecular modeling of odorants because thermally accessible structures may differ from the potential-energy minima identified in conformational searches. Here, we combine automated conformational exploration, multistructural thermodynamics, and descriptor-based statistical analysis to characterize the conformational ensembles of three flexible acyclic terpenic alcohols: geraniol, nerol, and linalool. The conformational searches identify large numbers of conformers (119, 88, and 83 for geraniol, nerol, and linalool, respectively), but only a subset of these structures contributes substantially to the finite-temperature equilibrium ensemble. Across the three systems, entropy-related contributions tend to shift the equilibrium toward more extended arrangements than those favored electronically, leading to Gibbs free-energy minima at 310 K that can differ from the corresponding potential-energy minima. Descriptor–energy correlation analyses further show that, among the descriptors considered, global shape exhibits the most consistent association with thermodynamic stabilization, rather than individual local hydroxyl-mediated contacts; decomposition of the Gibbs free energies indicates that this trend is predominantly vibrational in origin. Principal component and clustering analyses reveal that the ensembles are better described as continuous conformational landscapes than as sharply separated structural families. These results highlight the limitations of relying only on potential-energy minima and support the use of ensemble-based, descriptor-guided molecular modeling strategies for flexible odorants and related acyclic terpenoids.