Research by Dr. Kshatresh Dubey from Shiv Nadar’s Chemistry Department Features Among JACS’ Most Influential Research Publications from India in the Past 25 Years

The rapid development of the field of computational chemistry over the past few decades has led to quantum leaps across several fields, from catalysis to drug design and development. At its core, computational chemistry deals with the prediction of molecular structure, behaviour, and interactions using software that incorporates the principles of theoretical chemistry. The chief advantage of the field lies in its use of mathematics to simulate molecular behaviours that may not otherwise be understood through lab experiments. In 2023, the Shiv Nadar Institution of Eminence (SNIoE) launched ‘Magus’—a High-Performance Computing Cluster—to facilitate research by delivering powerful computing resources that can process enormous amounts of data quickly and accurately. With the introduction of Magus, computational chemistry research at SNIoE has accelerated at a tremendous pace. At the forefront of the Chemistry Department’s computational chemistry research is Assistant Professor Kshatresh Dubey, whose research was recently selected by the Journal of the American Chemical Society (JACS) to be part of the collection of the most influential chemistry research published from India in the past 25 years.

The prestigious accolade relates to Dr. Dubey’s 2020 paper, “Solvent Organization and Rate Regulation of a Menshutkin Reaction by Oriented External Electric Fields are Revealed by Combined MD and QM/MM Calculations”, which investigates how the application of an external electric field can be used to drive catalysis in the production of quaternary amine salts. In an exclusive interview, Dr. Dubey explained the preliminary idea behind the research, “Since chemical reactivity, at a fundamental level, is the (re)sharing and (re)paring of valence electrons, we believe that an application of an electric field along the reaction axis may perturb the pattern of electron movement and, hence, the chemical reactivity.”

To better understand the efforts behind the research, Dr. Dubey asks us to consider two basic components of modelling a chemical system—the first, a ball and stick model and the second, electron clouds. In a ball and stick model, atoms are represented by balls, and sticks represent the bonds between them. The length of the stick determines the strength of the bond etc. This approach is referred to as molecular mechanics (MM) and is quite clearly defined. On the other hand, there is the quantum mechanics (QM) perspective, which considers electrons as a wave function. This gives rise to an ‘electron cloud’ around the atom that depicts the probability of an electron being in a given location around the atom. While this may give a more nuanced model, the computational effort of calculating the wave functions for all the electrons in a system can become cumbersome. “If we’re going to think about a bigger system, like a protein, then we can’t calculate the electron clouds’ wave function of the entire complex. So, in that case, we can think basically about their conformation, if it’s being tweaked or if the atoms are just being rotated—we can think about their movements, and that can be treated by MM,” says Dr. Dubey. “But when we consider reactivity, we have to think of the sharing of electrons. That means we can’t study it using MM, but we need to apply QM instead. We believe that if there’s some combination, we can apply both MM and QM methods. So, the conformational changes can be made with MM methods and QM reactivity.” These mixed QM/MM methods can be applied by a range of software. The mixed method of QM/MM also provides a computational advantage, as MM tends to be much quicker and less computationally intensive than QM. 

Dr. Dubey’s research indicated that the production of quaternary amine salts through the well-defined Menshutkin reaction can be catalysed by an externally applied electric field alone as long as it can overcome the internal electric field generated by the solvents used in the reaction. Speaking on the applicability of the research, Dr. Dubey mentions that the research could have a huge impact on future industrial chemical processes. “Now, we are thinking about greener and sustainable chemistry more. Most of the time, to catalyse a reaction, we use some heavy metals, which are toxic or not good for the environment. But our research shows that this method (using an electric field) can enhance the reactivity significantly.” Extending the research to his current area of focus, which is enzymes, he emphasised that the application of an electric field in this manner can result in reactions that are new to nature.

“The limitation of these techniques is that it (developing this approach to catalysis) is experimentally very hard to achieve. However, we published our computational research in 2020, and we were very happy that within three years, this computational prediction was verified experimentally. One thing is clear: it (computational predictions) actually gives you the direction in which we have to move,” clarifies Dr. Dubey when asked about the advantages of this kind of computational research. 

Expanding on the current directions of the research, Dr. Dubey mentions that he is keen to work on new-to-nature enzymatic reactions. “New-to-nature reactions are those that can’t be done using natural enzymes. Now, what we want to do is to make enzymes to perform these new-to-nature reactions, such as plastic degradation. If we can, somehow, design these enzymes and put them in bacteria, we can also tackle some of the world’s problems. We are working on this kind of enzyme-designing in our lab at Shiv Nadar University.”

The research on the catalytic potential of an electrical field can also be applied to separate racemic mixtures, i.e., mixtures of molecularly similar but conformationally different compounds. The separation of racemic mixtures is quite complicated. However, if an electric field can be applied to the mixture such that each conformation of the compound experiences a different dipole due to different conformation, then each conformation will move in a different direction, thereby making the mixture easier to separate. “This is something that we can actually apply in the industry. We are trying to develop protocols where we can do such types of things,” explains Dr. Dubey.

According to Dr. Dubey, interdisciplinary research will be key to solving these kinds of challenges. “I started with a Master’s in Electronics, not even core physics, and then I shifted to biophysics. Being a physicist, I had a different insight. I think this is why everyone is encouraging interdisciplinary research now. Because when people are from a different background when they come into a new zone or subject, it gives new insight, and it creates a driving force to the research.”

The field of computational chemistry is growing rapidly, and SNIoE’s exemplary facilities are only adding to that. Having guided several successful Ph.Ds. who have all gone on to stellar placements, Dr. Dubey is looking forward to attracting more students and researchers to this fascinating and dynamic field. “The key to a Ph.D. is motivation. As a mentor, I try to keep my students motivated as well. And I think this improves the relationship between a PI (principal investigator) and the students as well. I believe that the well-being of the students is also one type of success for my group,” concludes Dr. Dubey.

We look forward to seeing what Dr. Dubey and his students do next!