Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Jul 16;14(14):2494.
doi: 10.3390/foods14142494.

Decoding the Molecular Mechanisms of Menthol Isomer Perception Based on Computational Simulations

Mengxue Wang  1   2   3 , Fengge Wen  1   2   3 , Lili Zhang  3 , Baoguo Sun  3 , Jianping Xie  1 , Shihao Sun  1 , Yuyu Zhang  3
Affiliations

Decoding the Molecular Mechanisms of Menthol Isomer Perception Based on Computational Simulations

Mengxue Wang et al. Foods. .

Abstract

The flavor characteristics, perception, and molecular mechanisms of eight menthol isomers were investigated by sensory analysis combined with computational simulations. The sensory analysis results show significant differences in the odor profiles of the different menthol isomers. Among them, L-menthol shows a pleasant, sweet, and mint-like odor with a distinct freshness and no off-flavors, whereas the remaining seven isomers were interspersed with negative odors (musty, herbal, or earthy aromas). L-menthol and D-menthol had the lowest detection thresholds of 5.166 and 4.734 mg/L, respectively. The molecular docking results of the menthol isomers with olfactory receptors (Olfr874, OR8B8, and OR8B12) indicate that hydrogen bonding and hydrophobic interactions were the key binding forces. The binding energy ranged from -7.3 to -5.1 kcal/mol. Residues His-55 (Olfr874), Thr-56 (Olfr874), Leu-55 (OR8B8), Tyr-94 (OR8B8), Thr-57 (OR8B8), Phe-199 (OR8B12), and Ser-248 (OR8B12) with high frequencies particularly contributed to the recognition of menthol isomers. These findings contribute to a deeper understanding of the olfactory perception mechanism of menthol and provide data support for the development and precise application of minty odorants.

Keywords: detection threshold; isomers; menthol; molecular docking; sensory evaluation.

PubMed Disclaimer

Conflict of interest statement

The authors declare that there are no conflicts of interest.

Figures

Figure 1
Figure 1
The radar plots of the sensory evaluation of eight menthol isomers. (A): L-menthol; (B): D-menthol; (C): L-neomenthol; (D): D-neomenthol; (E): L-isomenthol; (F): D-isomenthol; (G): L-neoisomenthol; (H): D-neoisomenthol. C1–C5: The five concentrations of the sample (from high to low).
Figure 2
Figure 2
Detection thresholds of eight menthol isomers. The vertical axis represents the probability of correct detection of odors by test subjects, and the horizontal axis represents the logarithm of odor concentration.
Figure 3
Figure 3
Multiple sequence comparison between mouse Olfr874 and direct human homologs OR8B8 and OR8B12. The 22 amino acid positions predicted by Man et al. [46] are marked with yellow boxes, and amino acid residues with <100% conservation are marked with green boxes. Transmembrane helices (TMHs) are indicated as large blue boxes.
Figure 4
Figure 4
Molecular docking results of the olfactory receptor OR8B8 with eight menthol isomers. (A): L-menthol; (B): D-menthol; (C): L-neomenthol; (D): D-neomenthol; (E): L-isomenthol; (F): D-isomenthol; (G): L-neoisomenthol; (H): D-neoisomenthol. a–c: The global, local enlarged, and 2D plots of the docking. d: Binding pocket.
Figure 4
Figure 4
Molecular docking results of the olfactory receptor OR8B8 with eight menthol isomers. (A): L-menthol; (B): D-menthol; (C): L-neomenthol; (D): D-neomenthol; (E): L-isomenthol; (F): D-isomenthol; (G): L-neoisomenthol; (H): D-neoisomenthol. a–c: The global, local enlarged, and 2D plots of the docking. d: Binding pocket.
Figure 5
Figure 5
Molecular docking results of the olfactory receptor OR8B12 with eight menthol isomers. (A): L-menthol; (B): D-menthol; (C): L-neomenthol; (D): D-neomenthol; (E): L-isomenthol; (F): D-isomenthol; (G): L-neoisomenthol; (H): D-neoisomenthol. a–c: The global, local enlarged, and 2D plots of the docking. d: Binding pocket.
Figure 5
Figure 5
Molecular docking results of the olfactory receptor OR8B12 with eight menthol isomers. (A): L-menthol; (B): D-menthol; (C): L-neomenthol; (D): D-neomenthol; (E): L-isomenthol; (F): D-isomenthol; (G): L-neoisomenthol; (H): D-neoisomenthol. a–c: The global, local enlarged, and 2D plots of the docking. d: Binding pocket.
Figure 6
Figure 6
Molecular docking results of the olfactory receptor Olfr874 with eight menthol isomers. (A): L-menthol; (B): D-menthol; (C): L-neomenthol; (D): D-neomenthol; (E); L-isomenthol; (F): D-isomenthol; (G): L-neoisomenthol; (H): D-neoisomenthol. a–c: The global, local enlarged, and 2D plots of the docking. d: Binding pocket.
Figure 6
Figure 6
Molecular docking results of the olfactory receptor Olfr874 with eight menthol isomers. (A): L-menthol; (B): D-menthol; (C): L-neomenthol; (D): D-neomenthol; (E); L-isomenthol; (F): D-isomenthol; (G): L-neoisomenthol; (H): D-neoisomenthol. a–c: The global, local enlarged, and 2D plots of the docking. d: Binding pocket.
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. Kamatou G.P.P., Vermaak I., Viljoen A.M., Lawrence B.M. Menthol: A simple monoterpene with remarkable biological properties. Phytochemistry. 2013;96:15–25. doi: 10.1016/j.phytochem.2013.08.005. - DOI - PubMed
    1. Merckel C., Pragst F., Ratzinger A., Aebi B., Bernhard W., Sporkert F. Application of headspace solid phase microextraction to qualitative and quantitative analysis of tobacco additives in cigarettes. J. Chromatogr. A. 2006;1116:10–19. doi: 10.1016/j.chroma.2006.03.010. - DOI - PubMed
    1. Casares N., Alfaro M., Cuadrado-Tejedor M., Lasarte-Cia A., Navarro F., Vivas I., Lasarte J.J. Improvement of cognitive function in wild-type and Alzheimer´s disease mouse models by the immunomodulatory properties of menthol inhalation or by depletion of T regulatory cells. Front. Immunol. 2023;14:1130044. doi: 10.3389/fimmu.2023.1130044. - DOI - PMC - PubMed
    1. Xu L., Han Y., Chen X., Aierken A., Wen H., Zheng W., Wang H., Lu X., Zhao Z., Ma C., et al. Molecular mechanisms underlying menthol binding and activation of TRPM8 ion channel. Nat. Commun. 2020;11:3790. doi: 10.1038/s41467-020-17582-x. - DOI - PMC - PubMed
    1. Takai Y., Touhara K. Enantioselective recognition of menthol by mouse odorant receptors. Biosci. Biotechnol. Biochem. 2015;79:1980–1986. doi: 10.1080/09168451.2015.1069697. - DOI - PubMed

LinkOut - more resources