Biomacromolecules, such as DNA, RNA, and proteins, are molecular machines that perform various cellular functions. The functions are often realized due to the ability of these biomolecules to undergo structural changes on relevant time scales. Sometimes, âmisfoldingâ of these biomolecules also generates structures that are toxic to the cells, leading to diseases. In this presentation, I will discuss my efforts toward understanding this structure-dynamics-function relationship of biomolecules using fluorescence spectroscopy and microscopy.
The first part of the presentation will focus on the biophysical mechanisms of protein aggregation diseases, especially on the aggregation of amyloid-β implicated in Alzheimerâs disease. I try to address three major questions: (I) which earliest aggregate of amyloid-β is toxic?1 (II) why is it toxic?2,3 and, (III) how is it toxic?4,5 Our results show that a key structural change at the earliest step of aggregation possibly drives amyloid-β toward the toxic pathway.
Next, I will introduce a new single-molecule fluorescence method called two-dimensional fluorescence lifetime correlation spectroscopy (2D FLCS),6 which provides a microsecond time resolution for studying biomolecular structural dynamics. This method, recently developed at my postdoctoral laboratory, is currently one of the most advanced single-molecule techniques. I will talk about my contributions in further advancing this cutting-edge method,7 and its application to biologically important macromolecules.8 Very recently, we applied 2D FLCS to elucidate the folding landscape and ligand binding mechanisms of prequeosine riboswitch, which revealed the molecular mechanism of its biological function, i.e., to regulate transcription in bacteria.8
In the final part of the presentation, I will provide a glimpse of my future research plan, which is to study the structure-dynamics-function relationship of non-coding RNAs. The particular focus will be on gene-regulatory small non-coding RNAs, such as microRNA, small interfering RNA, and riboswitches, which are important therapeutic targets.
[1] B. Sarkar, A. K. Das, & S. Maiti, Front. Physiol. 4 (84), 1 (2013).
[2] S. Nag# & B. Sarkar# et al, Phys. Chem. Chem. Phys. 15, 19129 (2013). (#equal contribution)
[3] B. Sarkar#, B. Chandra# & V.S. Mithu# et al, Angew. Chem. 53, 6888 (2014). (#equal contribution)
[4] B. Sarkar et al, Front. Physiol. 3 (414), 1 (2012).
[5] B. Sarkar# & A. Banerjee# et al. ACS Chem. Neurosci. 5(5), 329 (2014). (#equal contribution)
[6] K. Ishii, & T. Tahara, J. Phys. Chem. B 117, 11414 & 11423 (2013).
[7] B. Sarkar, K. Ishii, & T. Tahara, J. Phys. Chem. Lett. 10, 5536 (2019).
[8] B. Sarkar, K. Ishii, & T. Tahara, J. Am. Chem. Soc. 143, 7968 (2021).
LOCATION:Remote Video Conference END:VEVENT END:VCALENDAR