Ensemble-Based Descriptor Analysis of Flexible Odorants: Conformational Landscapes of Geraniol, Nerol, and Linalool
- 1Department of Chemistry, Universidad Autónoma de Madrid, Calle Francisco Tomás y Valiente, 7, 28049 Madrid, Spain
- 2Institute for Advanced Research in Chemical Sciences (IAdChem), Universidad Autónoma de Madrid, 28049 Madrid, Spain
- 3Departamento de Química Física, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
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.
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BibTeX
@article{cuadradobenavent2026ensemblebased,
title = {{Ensemble-Based Descriptor Analysis of Flexible Odorants: Conformational Landscapes of Geraniol, Nerol, and Linalool}},
author = {Beatriz Cuadrado-Benavent and Juan J. Nogueira and David Ferro-Costas},
journal = {The Journal of Physical Chemistry. a},
year = {2026},
month = oct,
doi = {10.1021/acs.jpca.6c04688},
url = {https://doi.org/10.1021/acs.jpca.6c04688},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Ensemble-Based Descriptor Analysis of Flexible Odorants: Conformational Landscapes of Geraniol, Nerol, and Linalool
AU - Beatriz Cuadrado-Benavent
AU - Juan J. Nogueira
AU - David Ferro-Costas
PY - 2026
DA - 2026/10/14
JO - The Journal of Physical Chemistry. a
DO - 10.1021/acs.jpca.6c04688
UR - https://doi.org/10.1021/acs.jpca.6c04688
AB - 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.
SN - 1089-5639
SN - 1520-5215
ER -