A small molecule chemical chaperone optimizes its unfolded state contraction and denaturant like properties

Scientific Reports
Sunny SharmaKrishnananda Chattopadhyay

Abstract

Protein aggregation is believed to occur through the formation of misfolded conformations. It is expected that, in order to minimize aggregation, an effective small molecule chaperone would destabilize these intermediates. To study the mechanism of a chemical chaperone, we have designed a series of mutant proteins in which a tryptophan residue experiences different local environments and solvent exposures. We show that these mutants correspond to a series of conformationally altered proteins with varying degree of misfolding stress and aggregation propensities. Using arginine as a model small molecule, we show that a combination of unfolded state contraction and denaturant like properties results in selective targeting and destabilization of the partially folded proteins. In comparison, the effect of arginine towards the folded like control mutant, which is not aggregation prone, is significantly less. Other small molecules, lacking either of the above two properties, do not offer any specificity towards the misfolded proteins.

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Citations

Jul 18, 2015·Environmental Research·Ryan ClantonGamal Akabani
Feb 10, 2017·The Journal of Physical Chemistry. B·Achinta SannigrahiKrishnananda Chattopadhyay
Feb 3, 2021·Journal of Personalized Medicine·Britt DelnoyMaria Estela Rubio-Gozalbo
Mar 13, 2020·Langmuir : the ACS Journal of Surfaces and Colloids·Animesh HalderSanat Karmakar
Dec 11, 2014·ACS Chemical Biology·Rohan DandageKausik Chakraborty

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Methods Mentioned

BETA
fluorescence correlation spectroscopy
fluorescence
fluorescence spectroscopy
FCS

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