Finding the dynamic key to the COVID-19 lock

Dr. Nikhil Tulsian’s interview with Bio Patrika hosting “Vigyan Patrika”, a series of author interviews. Dr. Nikhil, a co-first author of the recently published article in eLife, is a skilled biochemist who is interested in characterization of protein-protein interactions using a range of biophysical methods including mass spectrometry, fluorescence spectroscopy and cryo-electron microscopy. Currently, he is a joint postdoctoral fellow at Dept. of Biological Sciences and Dept. of Biochemistry in National University of Singapore. Dr. Nikhil obtained his Ph.D. from National University of Singapore in 2017 and completed his Master’s degree from University of Hyderabad in 2012. Here, Nikhil talks about his work on ‘SARS-CoV-2 S protein:ACE2 interaction reveals novel allosteric targets’ published in eLife (2021).

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

In this research paper, recently published in eLife, we have focused on understanding the effect of a human host receptor called ACE2 on Spike proteins, which are protrusions present on the surface of COVID-19 virus. Previous published studies show a static view of the Spike protein, but our research highlights its inherent dynamics and identify subtle structural changes during interaction of viral Spike protein with human ACE2 receptor. Using mass spectrometry and molecular dynamics, apart from observing the immediate effects of ACE2 on Spike protein, we were also able to observe long-range changes across other regions on Spike protein. This is particularly interesting as these regions are associated with the main function of Spike protein, where it undergoes significant change in its shape to be able to insert itself and hence the virus into human cells. Most antiviral strategies today, against COVID-19, involve the use of antibodies to block the interactions of Spike protein with human host. While this may not be completely effective against the virus, targeting the new sites proposed in our study, locks the virus and prevents it from entering the human cell.

Figure 1: COVID-19 virus infects human cells by a viral surface “Spike” protein (blue-orange). Inherently, this trimeric Spike protein gets cleaved at a specific site to two subunits A and B (left pathway). In human cells, subunit A of viral Spike protein binds to host ACE2 receptor (green). In our paper, we show that this complex formation induces changes across the Spike protein and promotes its cleavage to subunits A and B. We propose this as a novel target for antibody therapeutics against COVID-19.

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

The immediate consequence of our findings is the identification of alternate sites that should be targeted for weakening coronavirus. A combined approach of blocking the receptor binding sites and restricting flexibility of Spike would pave way for better therapeutic strategies against the COVID-19 virus. Such a tactic would be largely beneficial for prompt fighting against the coronavirus, which has infected people of all ages across the world. We are working on a follow-up research article that will discuss some of these aspects for effective inactivation of coronavirus, such as combinatorial antibody therapy. Moreover, the method we used, allows characterization of protein-protein interactions, which helps in deeper understanding of direct and indirect consequences associated with any virus-host systems.

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

For me, one of the exciting moments during my research was to learn that proteins undergo rapid shape-shifts forming a collection of different ‘forms’. This is referred to as a ‘conformational ensemble’, and is essential for proteins to sense changes in their environment and function correctly. This fundamental phenomenon widened my research interests at a molecular level. Proteins are very sensitive to any change in temperature, pH, salt content or mutation. Scientific ability to detect these changes of protein’s shape, and the intended affects on protein functions defines almost all cellular processes.

What do you hope to do next?

I’m interested in channeling the scientific skills I acquired to various topics like protein-protein interactions, biosimilars, antibody-discovery and therapeutics. For distant future, I would like to carry out application-based research and use artificial intelligence for developing new therapeutic methodologies.

Where do you seek scientific inspiration?

Rapid progress in various scientific fields and the emergent technologies for executing any experiment we could think of, keeps me on-the-edge to continue doing research. I’m also awed and inspired by looking at a living cell as a whole, wherein different intracellular aspects function together to maintain a balanced-state and adapt efficiently to any external factor. 

How do you intend to help Indian science improve?

Indian science has reached great heights in recent times and is performing well. It provides a stiff competition to the global scientific community. Creating a more effective research ecosystem and focusing more on research to tackle practical issues would boost India’s science tremendously. I am keen to be part of Indian biotech industry by applying my scientific and research management skills, and advance scientific pursuit by adopting new technologies for mutual scientific progress. Another key factor improving science in India necessitates establishing academic-industrial collaborations to develop more vibrant young-Indian scientists.

Reference
Raghuvamsi PV, Tulsian NK ,Samsudin F, Qian X, Purushotorman K, Yue G, Kozma MM, Hwa WY, Lescar J, Bond PJ, MacAry PA, Anand GS. SARS-CoV-2 S protein:ACE2 interaction reveals novel allosteric targets. Elife. 2021 Feb 8;10:e63646.
doi: 10.7554/eLife.63646.

Email: nikhil.tulsian@nus.edu.sg

Prof. Ganesh S Anand lab :
https://www.dbs.nus.edu.sg/lab/anand_lab/index.html

Edited by: Pratibha Siwach and Nivedita Kamath (Copy Editor, Volunteer, Biopatrika)

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