Nilimesh Das

Primarily, I got my formal education in chemistry. I got my training in various fluorescence-based ultrafast and single molecular level spectroscopy, assembling and disassembling of confocal set-up, a little bit of analytical modeling, and protein biochemistry. Now, I aspire to work on more advanced research problems using the cutting-edge facility in Harvard Medical School.

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I joined IIT Kanpur, one of India’s most reputed research centers, in 2015 with my own national fellowship after finishing my master’s studies at Presidency University, Kolkata as the gold medalist. I started working on protein behavior in the crowded milieu to understand the cellular phenomenon in the cell-like environment instead of buffer. Having my formal education in chemistry, I started seeing this essential biological problem from the viewpoint of a photo chemist and became more curious about the mechanistic aspect of this problem. Traditionally, the macromolecular crowding effect is explained by a delicate balance between the stabilizing entropic effect and the stabilizing or destabilizing enthalpic effect. However, this traditional crowding theory cannot explain experimental observations like negative entropic effect and entropy-enthalpy compensation. I made two fundamental claims regarding the mechanism of macromolecular crowding. Firstly, I recognized that the modulation in crowded milieu might also originate from the pressure exerted on the biomolecules by the crowders. Secondly, consideration of entropic and enthalpic modulation through crowder-induced distortion of associated water successfully explains the negative entropic part and entropy-enthalpy compensation. The role of water in controlling protein stability has been investigated by some of the very big names of physical chemistry. However, a proper relationship between these two parameters never really came off. My work detects that missing point, and shows that the relationship between associated water structure and protein stability should be better understood by individual entropic and enthalpic components instead of the overall stability. The generality of this approach is being tested taking various proteins and cosolvents in my Ph.D lab.

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In 2020, Covid hit hard, and our lab was closed for over a year. Like the whole world, this is a very hard time for me too. Academically, being an experimentalist, it wasn’t easy. However, during this time, I started reading and learning many things, like basic bioinformatics that are somewhat unrelated to my doctoral thesis. At this time, I got interested in molecular-level heterogeneity. Any dynamics generally follows Stokes-Einstein diffusion. I did an analytical modeling to predict and validate how such dynamics will be modulated in a heterogeneous system. Despite being an experimentalist, I published an original research paper without almost any data. There was a conventional method of detecting dynamic heterogeneity by the so-called log-log plot from its departure of slope from unity. I understood that such departures might arise from other reasons, notwithstanding molecular-level heterogeneity. I devised two strategies to detect such heterogeneity in translational and rotational diffusion. I expect this newly developed method will be adopted by researchers in this field soon.

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Currently, I forwarded such an idea of detecting heterogeneity to the heterogeneity of proteins. There are many excellent techniques to identify (and sometimes quantify) such heterogeneity, but their arduous instrumentation and rigorous data analysis prevent them from being applied universally. Moreover, most existing methods suffered drawbacks because of the coupled nature of protein conformation and environment. We developed a novel edge effect, i.e., the shift of excitation spectra at the blue edge of emission (which I termed as BEEmS), that can detect heterogeneity in protein without interference from surrounding. Most importantly, as the method is based on steady-state fluorimetry, its vast availability and simplicity in experiment and analysis might make it a routine method among researchers, especially in countries like India.

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I have a broad view of research, as I have been actively involved in almost all my doctoral lab projects. It created a good habit of connecting two apparently different problems and finding the solution. It could be found in several of my publications not related to my research field. In between, I visited Japan two times as a part of two different projects from DST and JSPS. I also partially guided three M.Sc. students in their master projects and directly monitored three junior Ph.D. students.

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After I submitted my thesis last year, I wanted a shift in my research field in the sense that I wanted to work on more relevant problems exploiting my background of doing basic science. I felt very strongly that there is a fundamental gap between the inherent complexity of biology and the simplicity that chemists often seek. I decided to shift my research area so as to bridge this gap. Currently, I am utilizing fluorescence correlation spectroscopy (FCS) to detect the presence of aggregates in the blood samples of patients having renal amyloidosis. We only have primary data. However, we hope that we are on the verge of devising a non-invasive technique for the detection of amyloidosis.

Now, I want to take one step ahead and work on cutting-edge research using cutting-edge techniques. I will be joining Sua Myong Lab in HMS.