Bio Patrika interviews Dr. Athavale on his thoughts about “decades-old mystery about the mechanism of an iconic transformation in organic chemistry”

Dr. Soumitra V. Athavale’s interview with Bio Patrika hosting “Vigyan Patrika”, a series of author interviews. Dr. Athavale is currently a Postdoc in the lab of Prof. Frances Arnold (2018 Nobel Prize in Chemistry) at Caltech, USA. As part or PhD, Dr. Athavale has published papers entitled “Demystifying the asymmetry-amplifying, autocatalytic behaviour of the Soai reaction through structural, mechanistic and computational studies” published in Nature Chemistry and “Structural Contributions to Autocatalysis and Asymmetric Amplification in the Soai Reaction” published in J. Am. Chem. Soc. as a first author. Dr. Athavale is also cowinner of Merck Compound Challenge 2020.

How would you explain your paper’s key results to the non-scientific community?

Organic molecules are three-dimensional structures and most often can exist as mirror images of each other, like a right-handed and left-handed glove. Yet, just as these gloves cannot be superimposed on each other, these molecules are distinct. Intuitively, one would expect that the distribution of right-handed and left-handed molecules should be the same and this is indeed found in most cases. However, the biological world is amazingly skewed in its representation and is dominated by only one kind of molecule. The origin of this biological ‘homochirality’ is a profound unsolved question in science. How can such a symmetry breaking occur and produce an excess of only one kind of mirror image molecules?

In 1995, a Japanese chemist – Prof. Kenso Soai discovered an astonishing reaction where this can happen. The cause is a phenomenon called ‘asymmetric autocatalysis.’ Each mirror image product catalyzes its own formation while also inhibiting the formation of the other. As the reaction proceeds, one side gains the upper hand and ultimately dominates – leading to symmetry breaking. After this discovery, many researchers have attempted to understand how this phenomenon occurs at the molecular level – what are the catalyst structures, how does the autocatalysis progress? But for more than two decades, the mechanism has remained a mystery.

After four years of investigations, culminating into my PhD, we now present the mechanistic details of the Soai reaction and demystify the phenomenon of asymmetric autocatalysis. This work has been published in two papers (Nat. Chem. 2020, 12, 412-423 and JACS, 2020, 142, 18387-18406). After detailed experimental, structural and computational studies, we demonstrate how four molecules of the same handed reaction product combine to form a tetrameric complex. This complex is the autocatalyst. It interacts with the reactants and in an enzyme-like manner, produces the same handed product as itself. We also show how it inhibits the formation of the other mirror-image product. The main results in the Nature Chemistry paper were followed up by more details in the JACS article. In summary, we make a significant contribution in resolving a decades-old mystery about the mechanism of an iconic transformation in organic chemistry.

Figure 1. Schematic of Soai reaction.

“[…] we make a significant contribution in resolving a decades-old mystery about the mechanism of an iconic transformation in organic chemistry.”

What are the possible consequences of these findings for your research area?

Our findings shed light on how asymmetric autocatalysis takes place in the Soai reaction. It now provides a model for designing new transformations that show this effect.

What was the exciting moment (eureka moment) during your research?

There were a couple of them. The Soai reaction was restricted to pyrimidine substrates, which presented a lot of challenges for mechanistic studies. The first important breakthrough was discovering that pyridine systems were also competent – this led to some simplification and the system was more tractable. A lot of the work involved meticulous NMR spectroscopy. For a long time, I could not figure out how to explain the data but one day, the NMR pattern of one of the intermediate structures was so compelling that it immediately revealed how the tetrameric catalyst was forming. This critical insight was the foundation for proposing a model for the autocatalyst function.

What do you hope to do next?

After my PhD studies, I have now joined the lab of Prof. Frances Arnold at the California Institute of Technology (Caltech), USA. I am exploring protein directed evolution to discover new biocatalysts. I aspire to continue in academia and do more chemistry research in the future.

Where do you seek scientific inspiration?

Right from a young age, I was inspired by stories of scientists and their achievements. I am always excited when I see a beautiful result or natural phenomenon and learn more about it. I wonder what the background and circumstances of the discovery and the personalities behind the science were. I am also inspired by great books, which I believe greatly influence our scientific philosophy. In my formative years, I remember how I was enamored the two excellent textbooks – Organic Chemistry by Morrison and Boyd, and Biochemistry by Lehninger that made a critical impact on my thinking. For me, beauty and elegance in science is the ultimate inspiration and it comes in the form of great scientists and their immortal experiments.

How do you intend to help Indian science improve?

As an Indian scientist, doing the highest quality research and succeeding will inspire fellow countrymen (and others) to pursue their passions. One of the reasons Western universities are doing so well is that extraordinary people have given their lives to building departments of excellence. If given a chance, I will love to do research in India and contribute to further developing the scientific ecosystem.

References

Athavale S V, Simon A, Houk K N and Denmark S E. Demystifying the asymmetry-amplifying, autocatalytic behaviour of the Soai reaction through structural, mechanistic and computational studies. Nat. Chem. 12, 412–423 (2020).

Athavale S V, Simon A, Houk K N and Denmark S E. Structural Contributions to Autocatalysis and Asymmetric Amplification in the Soai Reaction. J. Am. Chem. Soc. 142, 18387-18406 (2020).

Author introduction and research interests

Born and raised in Pune, India, I completed my B.S.-M.S. in Chemistry and Biology from the Indian Institute of Science Education and Research (IISER) Pune. During this time, I worked with Prof. Harinath Chakrapani and Prof. Sanjeev Galande to get my initial training in organic chemistry and molecular biology. In Fall 2014, I joined Prof. Scott Denmark’s group at the University of Illinois, Urbana-Champaign. My PhD research focused on organic synthesis and elucidation of mechanistic pathways in asymmetric autocatalytic reactions, especially the Soai reaction. Since November 2019, I am working as a postdoctoral scholar in Prof. Frances Arnold’s lab at Caltech, with a focus on pushing the boundaries of synthetic nitrene chemistry with hemeproteins. I am broadly interested in asymmetric catalysis, biocatalysis and molecular evolution, especially in complex systems.

Email: athavale@caltech.edu

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