Proteins are functional entities in all living systems. They perform numerous functions including catalysis of chemical reactions, transport of ions and molecules, coordination of motion, provision of mechanical support, generation and transmission of nerve impulses, and control of growth and differentiation. Inside the living cells, a protein molecule is synthesized as a linear unfolded polypeptide chain which must fold to a functional three dimensional structure. An error in this process leads to fatal diseases. Our research is focused on understanding the rules which govern the folding, unfolding and aggregation of proteins. We employ a highly interdisciplinary approach to address these problems by combining the tools of quantitative biophysical chemistry, protein engineering, molecular biology, and steady-state and time-resolved spectroscopic methods, including fluorescence resonance energy transfer technique, infrared spectroscopy, NMR, Hydrogen-deuterium and thiol-disulfide exchange methodologies coupled to mass spectrometry. The long term goal of our research is to understand how the three-dimensional functional structure of a protein and its dynamic energy landscape is encoded by its linear sequence of amino acids.

In one of our recent work on protein folding we have demonstrated that pH induced structural perturbation in a multi-domain protein leads to the formation of an intermediate state in which side-chain packing inside the hydrophobic core of two of the domains is disrupted but their core is dry. This result allowed us to dissect out the energetic contribution of the hydrophobic effect and the van der Waals forces in the stability of different domains.


 

Selected Publications:

Acharya N, Mishra P And Jha SK, Evidence for Dry Molten Globule-Like Domains in the pH-Induced Equilibrium Folding Intermediate of a Multi-Domain Protein, J. Phys. Chem. Lett., 7, 173 - 179 (2016)

Jha SK And Marqusee S, Kinetic evidence for a two-stage mechanism of protein denaturation by guanidinium chloride, Proc. Natl. Acad. Sci. USA., 111, 4856 - 4861 (2014)

Jha SK, Ji M, Gaffney KJ And Boxer SG, Direct measurement of the protein response to an electrostatic perturbation that mimics the catalytic cycle in ketosteroid isomerase, Proc. Natl. Acad. Sci. USA., 108, 16612 - 16617 (2011)