Research

Molecular recognition plays a central role in biology, and protein dynamics has been shown to be important in this process. Solution NMR has an arsenal of experimental techniques for recording dynamics of biomolecules in different timescales at atomic resolution. The focus of my research has been on the role of dynamics in the functioning of biomolecules, specifically, the role played by dynamics in protein-protein/ligand interactions. It is highly debated whether conformational changes happen before ligand binding to produce a binding-competent state (conformational selection) or are caused in response to ligand binding (induced fit). In the case of the neuronal calcium sensor protein recoverin, which has a favorable rate of binding of ~ 30 s^-1, we could show comprehensively that the binding follows a conformational selection mechanism (Chakrabarti et al 2016). The slow rate of binding allowed us to employ stopped-flow kinetics for direct measurement of rates. However, this investigation becomes more difficult in other systems as the rates in question become faster and beyond the detection limit of many biophysical techniques. Therefore, in case of the ubiquitin-conjugating system we had to resort to molecular dynamics simulation, along with NMR relaxation dispersion experiments, to show dynamic origin of allostery of binding to its partner protein, the ubiquitin-ligase (Chakrabarti et al 2017). Currently we are extending the investigation to the model protein ubiquitin, which involves development of both NMR methodology and computational algorithm (Chakrabarti et al 2022).

Kalyan S. Chakrabarti, Simon Olsson, Supriya Pratihar, Kerstin Overkamp, Ko On Lee, Vytautas Gapsys, Kyoung-Seok Ryu, Bert L. de Groot, Frank Noe, Stefan Becker, Donghan Lee, Thomas R.Weikl, Christian Griesinger, "A litmus test for classification of recognition mechanisms of transiently binding proteins" Nature communication (2022) 13: 3792.

Kalyan S. Chakrabarti, Jess LI, Ranabir Das, R. Andrew Byrd, "Conformational dynamics and allostery in E2:E3 interactions driving ubiquitination: gp78 and Ube2g2", Structure (2017) 25 : 794-805.

Kalyan S. Chakrabarti, Roman Agafonov, Francesco Pontiggia, Renee Otten, Matthew K. Higgins, Gebhard F. X. Schertler, Daniel D. Oprian and Dorothee Kern, “Conformational selection in a protein-protein interaction by dynamic pathway analysis”, Cell Reports (2016) 14: 32-42.