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Quantification of Entropic Excluded Volume Effects Driving Crowding-Induced Collapse and Folding of a Disordered Protein

Rajendran, D and Mitra, S and Oikawa, H and Madhurima, K and Sekhar, A and Takahashi, S and Naganathan, AN (2022) Quantification of Entropic Excluded Volume Effects Driving Crowding-Induced Collapse and Folding of a Disordered Protein. In: Journal of Physical Chemistry Letters, 13 (13). pp. 3112-3120.

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Official URL: https://doi.org/10.1021/acs.jpclett.2c00316


We investigate the conformational properties of the intrinsically disordered DNA-binding domain of CytR in the presence of the polymeric crowder polyethylene glycol (PEG). Integrating circular dichroism, nuclear magnetic resonance, and single-molecule Förster resonance energy transfer measurements, we demonstrate that disordered CytR populates a well-folded minor conformation in its native ensemble, while the unfolded ensemble collapses and folds with an increase in crowder density independent of the crowder size. Employing a statistical-mechanical model, the effective reduction in the accessible conformational space of a residue in the unfolded state is estimated to be 10 at 300 mg/mL PEG8000, relative to dilute conditions. The experimentally consistent PEG-temperature phase diagram thus constructed reveals that entropic effects can stabilize disordered CytR by 10 kJ mol-1, driving the equilibrium toward folded conformations under physiological conditions. Our work highlights the malleable conformational landscape of CytR, the presence of a folded conformation in the disordered ensemble, and proposes a scaling relation for quantifying excluded volume effects on protein stability. © 2022 American Chemical Society.

Item Type: Journal Article
Publication: Journal of Physical Chemistry Letters
Publisher: American Chemical Society
Additional Information: The copyright for this article belongs to American Chemical Society
Keywords: Conformations; Energy transfer; Entropy; Proteins, Conformational properties; Crowd density; Disordered proteins; DNA-binding domain; Energy transfer measurement; Excluded volume effects; Folded conformation; Foldings; Resonance energy transfer; Single molecule, Dichroism
Department/Centre: Division of Biological Sciences > Molecular Biophysics Unit
Date Deposited: 18 May 2022 06:27
Last Modified: 18 May 2022 06:27
URI: https://eprints.iisc.ac.in/id/eprint/71817

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