Quantum Tunneling in Natural Product Biosynthesis

In the early 20th century, serious interest and investigation began concerning the biosynthesis of the cannabinoid natural product family, now numbering more than 100 diverse members. Although technical knowledge gaps still persist in this area, over the past century of active exploration much has been achieved regarding this fascinating topic. The intriguing Cannabis trichome was identified as the predominant cannabinoid biosynthetic locus ¹ and many of its key enzymes have been discovered along with their structural characterization and some details concerning their genetic control. ² However, amid all this impressive progress one very unique and impactful discovery has just been reported.

Recently, an extremely novel cannabinoid publication appeared with notable computational chemists Doubleday and Greer as lead authors. ³ Having extensive experience in quantum mechanics applied to chemical reactions, ⁴ these investigators skillfully employed their powerful computational tools to interrogate the biosynthesis of tetrahydrocannabinol (THC) from a fresh in silico perspective. Remarkably, they discovered a significant degree of quantum “tunneling” involved in the THC enzymatic steps. Furthermore, their work resulted in the identification of a heretofore undetected component in the THC biosynthetic scheme. A definition of tunneling is useful to consider here and it has been described ⁵ as a “quantum mechanical phenomenon whereby particles can penetrate and pass areas of configuration space with a potential energy higher than their total energy.” Operative for electrons ⁶ as well as hydrogen ⁷ and even heavier atoms, tunneling explains both unexpected chemistry results and surprisingly accelerated chemical reaction rates, especially at very low temperatures.

Although it is beyond the scope of this discussion to explain the very detailed quantum mechanical calculations of the seminal 2022 paper, it is essential to underscore its special importance. After an exhaustive literature search of recent cannabinoid reviews along with careful mining of the SciFinder® chemistry database, it seems that this article is the first time tunneling has been invoked as a participant in cannabinoid biosynthesis. More importantly, this novel finding extends far beyond just the cannabinoid natural product collection. A further literature search reveals that tunneling has only been infrequently probed in most natural product biosynthetic pathways. A rare natural product example is the hydrogen tunneling proposed in terpene cyclization, as indicated by a large temperature-independent kinetic isotope effect. ⁸

Currently, it appears that tunneling is often overlooked in the natural product biosynthesis area. However, awareness of potential tunneling in natural product biosynthesis is important because of mounting evidence that tunneling may even be a controlling factor in some surprising reaction rates. ⁹ A Reviewer of this Letter aptly pointed out that the theoretical calculations predicting tunneling should also be followed up with experimental confirmation. Returning to our initial discussion entry point for a possible future direction example, a computational biosynthesis exploration of the structurally complex minor cannabinoid dimer cannabitwinol ¹⁰ (Figure 1) would be fascinating and perhaps reveal whether tunneling is involved in its still mysterious origin?

Figure 1.

Cannabitwinol structure.