Structural biology/Structural chemistry has huge potential in various fields,  because chemists can design molecules with specific properties that are useful for a wide range of applications, from drug development to materials science.

Sriram Srinivasa Raghavan (PhD), our next pathbreaker, Postdoctoral Researcher at RIKEN Centre for Computational Sciences, a large scientific research institute in Kobe, Japan, works as part of the Computational Structural Biology team, to find suitable numerical solutions to problems in theoretical crystallography. 

Sriram talks to Shyam Krishnamurthy from The Interview Portal about his PhD in Biophysics and Crystallography from the University of Madras where he worked on protein engineering.

For students, biological research has diverse applications. We need more young researchers to be involved in this field to solve pressing problems in today’s world, especially those concerning energy, environment and water.

Sriram, Can you tell us about your early years?

I hail from the small town of Tenkasi (Tamil Nadu), situated at the foothills of Podhigaimalai, in the Western Ghats. However, I grew up in Chennai and various cities across India on account of my father’s transferable job. He worked in the Council of Scientific and Industrial Research (CSIR), Govt of India, as a result of which I got exposure to science from an early age. 

My intellectual curiosity started small, as a childlike wonder about nature and the phenomena that underlie the working of the things around me. As a child, I would spend hours watching channels such as National Geographic, Animal Planet, Discovery, BBC Earth, etc. Moreover, the rockets that were launched from Sriharikota, AP, always had a trajectory that could be viewed from my terrace, which became a source of perennial fascination to me, becoming the root of my interest in structural biology, which in later life became a quest to understand energy as a driving force. In simple terms, the expansion of gas upon combustion propels the rockets which is a redox reaction. In order to understand structure-led function, I decided to pursue biophysics.  

I was academically an average student, at my best, till my school days. But, my scientific interest was continuously stimulated by my surroundings- my growing up years in the CLRI Quarters in Adyar, Chennai, and its proximity to various premier institutions and organizations such as IIT Madras, IMSc, University of Madras, Anna University, Birla Planetarium, Snake Park (Guindy), etc. 

I initially wanted to become a wildlife conservationist, but as I grew up, I was inclined toward understanding the mysteries of nature. I would be engrossed in things as varied as the structure of insects and the taxidermy of squirrels, to more profound subjects such as gravity and astronomy, finally structural biology and biophysics. 

What did you do for graduation/post-graduation?

I completed my Bachelor’s and master’s degrees in physics from Madras Christian College, Chennai. I did my PhD in Crystallography and Biophysics from The University of Madras.

What made you choose such an offbeat, unconventional and unusual career?

I was always eager to understand how redox reactions work. Having a Physics background, I could understand the atomic orbitals of an atom, but was not able to understand the overall kinetics of a reaction. For example, regarding combustion reaction- I remember asking lay questions to my friend Paul Daniel during my Master’s, such as what are the chemical constituents of wood, how does it produce energy on burning? I could not understand it until I completed my PhD, that the structure of a material performs its function, and in wood, it is the lignin and cellulose. The decomposition of bonds causes the release of energy. In simpler terms, it can be understood as molecular fission (splitting up into constituents). 

As students, we are fascinated with Nobel Laureates, for their work contributions that have made them a Nobel laureate. Similarly, I was fascinated by Indian Nobel laureates namely, Sir C. V. Raman– Physics(1930), Har Gobind Khorana -Medicine(1968),Subrahmanyan Chandrasekhar – Physics(1983),Venkatraman Ramakrishnan – Chemistry(2009). 

During my masters, I remember attending informal lectures conducted in astronomy about Subrahmanyan Chandrasekhar in The Institute of Mathematical Sciences. Similarly, I was primarily inspired by the work of the Nobel Laureate, Prof. Venki Ramakrishnan in the field of structural biology, leading me to pursue my PhD in Crystallography at the University of Madras. 

This department was established by the world-renowned crystallographer, Prof. G.N. Ramachandran, who was a student of the great Sir C.V. Raman. It was a matter of great privilege for me to pursue my doctoral studies in such an esteemed department which has been visited by as many as thirteen Nobel Laureates. 

I was introduced to this department by Dr. V.Subramanian, Chief Scientist, CLRI, to Prof Velmurugan, the Head of the Department, who had formerly worked with Herbert Hauptman, a Nobel Laureate. Since he was on the brink of retirement, I got an opportunity to work with one of his best students, Dr.K.Gunasekaran, who exposed me to the fields of crystallography and biophysics. I was also taking care of the departmental 400Mhz (Nuclear magnetic resonance) NMR machine maintained by Dr. S. Ganapathy (Retd. Scientist, National Chemical Laboratory), leading me to gain exposure to a technique apart from computational technique to which I got exposed from Dr. Subramanian’s lab during my masters. The afore-mentioned people played an instrumental role in my PhD. 

Tell us about your career path

Even today, solar technology is the talk of the town in enhancing energy efficiency. I was also awestruck by the efficiency of how plants produce energy during photoreactions. It was not till my PhD that I really understood the beauty of the intricate assembly of proteins that are involved in photosynthesis. One of the main protein complexes where photoreaction takes place is Photosystem II, encompassing the manganese cubane complex, which is the active center for water catalysis, releasing oxygen, proton and electron gradients and generating energy. 

Though I was interested in Photosynthesis, due to the incredible complexity of working with the same, I chose to work instead with a similar albeit small protein called Green Fluorescent Protein (GFP), at the behest of one  of my mentors, Dr. Ayyadurai, a scientist from CLRI. This protein has wide applicability as a biomarker. GFP is a photoreceptive protein which has fluorescence emission upon light excitation. This protein was first extracted from jellyfish, and the application of this protein as biomarker was awarded the Nobel prize to Prof.Osamu Shimomura, Prof.Martin Chalfie and Prof.Roger Tsien. Though the concept of this protein is already known, my project mainly involved protein engineering in understanding the mechanism of the protein upon incorporation of non-standard amino acids. 

In order to address some questions in the research, I had to use advanced sophisticated instruments for which I had the privilege of visiting institutes like the Centre for Biomedical Research, Lucknow (CBMR), Indian Institute of Science (IISc), Bangalore, Raja Ramanna Centre for Advanced Technology (RRCAT), Indore.

How did you get your first break?

I got my first breakthrough in my research when my crystal data (collected by Dr.Jaimohan, Scientist, CLRI) was successfully  collected from  elettra beamline, Italy. After the structure was solved, I published my paper, and was awarded my doctoral degree in 2019. Consequently, I got an opportunity to work with one of the pioneering structural biologists in India, Prof. M.V.Vijayan(IISC), a PadmaShree awardee, who worked with the Nobel Laureate, Dr. Dorothy Hodgkin, who had worked on the structure of insulin. He had motor neuron disorder like Dr.Stephen Hawking. Despite all difficulties, Prof Vijayan pursued his research till his demise. I consider myself fortunate to have worked with a great personality like him. I think a few things that a student should inculcate is to be curious, to ask questions (even if they sound silly). When you get the answers to them even after years, it makes you grow and want to continue the quest or journey to understand more. Everyone has a different capacity to understand and grasp knowledge. So, it is always okay for me if I do not know something, but I am ready to learn more provided it makes me curious. 

The key to success lies in constantly evolving and adapting one’s skill set, regardless of country or job. Failure is a natural part of the journey, and success often comes after many failed attempts. During my PhD, I faced numerous failures and setbacks, but thanks to the support of my role model (my beloved father), I built a workstation (worth two lakh rupees) with the help of people like Mr.Ganesh (Southern Enterprise), Mr.Shinde (Asus), which initiated my programming skills and eventually helped me complete my research(PhD). 

I am currently working on XFEL data processing technique and from PhD days I was fascinated to work on it. There are only five such facilities in the world and SACLA at RIKEN Harima Institute is one of the most advanced XFELs in the world. By 2030, India probably will have its own XFEL facility. From my PhD days I was eager and hoping to work in this institute, I am grateful to my mentors and excited to pursue my journey in this field. 

What were some of the challenges you faced? How did you address them?

One of the challenges that every researcher in India faces is the lack of funding for experimental support. Fields such as mine are plagued by greater failure rates and experimental costs. Therefore, I chose to deal with this problem by working more towards the computational side than the experimental side, to get a greater insight into the systems underlying the workings of the field. This helped me a lot during the onset of the pandemic during Covid 19.

Where do you work now? What problems do you solve?

I currently work at RIKEN, which is a large scientific research institute in Japan. To be specific, I work in the RIKEN Centre for Computational Sciences, Kobe, Japan which previously held the title of having the fastest supercomputer in the world (Fugaku). I work in the institute in the role of a Postdoctoral Researcher, in a Computational Structural Biology team under the aegis of Dr Florence Tama and Dr Osamu Miyashita.  A typical day at work entails finding suitable numerical solutions to problems in theoretical crystallography. 

In order to explain crystallography, I would like to say a little about structure-function relationship. 

Structure and function relationship is critical for designing any molecules with specific properties. For example, the shape and orientation of atoms in a molecule can affect its reactivity, physical and chemical properties. The structure of atoms and molecules determines their behavior in chemical reactions and can be used to understand complex chemical processes and reactions. The structure of the materials also determines its electronic and magnetic properties and can be used to engineer materials with specific properties, such as semiconductors for electronic devices. By understanding the relationship between structure and function, chemists can design molecules with specific properties that are useful for a wide range of applications, from drug development to materials science.

Now to study the structure(and to gain insights to function)  three techniques are widely used, namely- 1. Electron microscopy (TEM,SEM,HRTEM etc.), 2. Crystallography and 3. Nuclear magnetic resonance spectroscopy. This video from Protein data bank can be give a basic overview with example to understand.  

Crystallography or X-ray crystallography is a scientific field that studies the arrangement of atoms in crystals, which is a  broadly used technique to determine the structure of materials. Once the structure is known, physical and chemical properties can also be determined to aid in understanding the function. 

I try to understand a small chunk of such a broad field at my pace using experimental and theoretical approaches.  

How does your work benefit society? 

Structural biology/Structural chemistry has huge potential in various fields such as drug discovery, catalysis, energy, and the environment- which have major, life-changing ramifications. It has diverse applications from plastic degradation using PETase enzyme to making structure-based drug design & development. It would be great if a lot of students and young researchers are involved in this field to solve pressing problems in today’s world, especially those concerning energy and water.

Tell us an example of a specific memorable work you did that is very close to you!

My work during my PhD days when I had the opportunity of working with Dr. Dinesh Kumar, a scientist at CBMR, Lucknow; where I was involved in protein labelling of GFP (Green Fluorescent Protein) using NMR (Nuclear Magnetic Resonance), is particularly memorable to me along with my postdoctoral days in prof. Vijayan’s Lab. 

Your advice to students based on your experience?

My advice to Indian students is – ask the right questions and work towards addressing them. I would insist that Indian students get inspired by Japan for their perseverance as I always was. The country which has limited natural resources, having the highest number of natural calamities, has contributed immensely to the world. They host several modern technologies, but still are very humble by nature. 

Future Plans?

I would like to continue working in the same field of Structural Chemistry/Biology for the rest of my life, adapting to and incorporating the ongoing changes wrought by Artificial Intelligence to take a small step forward in addressing key problems such as energy, water catalysis, drug discovery, etc.