title: A small molecule chemical chaperone optimizes its unfolded state contraction and denaturant like properties.
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.
authors.affiliation: Structural Biology and Bioinformatics Division, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata 700032.
authors.forename: Sunny
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Structural Biology and Bioinformatics Division, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata 700032.
authors.forename: Suparna
authors.initials: S
authors.lastname: Sarkar
authors.affiliation: Structural Biology and Bioinformatics Division, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata 700032.
authors.forename: Simanta Sarani
authors.initials: SS
authors.lastname: Paul
authors.affiliation: Infectious diseases and Immunology Division, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata 700032.
authors.forename: Syamal
authors.initials: S
authors.lastname: Roy
authors.affiliation: Structural Biology and Bioinformatics Division, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata 700032.
authors.forename: Krishnananda
authors.initials: K
authors.lastname: Chattopadhyay
mesh_terms: D001120:Arginine / Q000737:chemistry / Q000235:genetics; D007891:Leishmania / Q000378:metabolism; D007896:Leishmaniasis / Q000276:immunology / Q000517:prevention & control; D054332:Leishmaniasis Vaccines; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism*; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000737:chemistry*; D050505:Mutant Proteins / Q000737:chemistry; D009154:Mutation; D011487:Protein Conformation; D011489:Protein Denaturation; D058767:Protein Unfolding; D015800:Protozoan Proteins / Q000235:genetics* / Q000378:metabolism*; D013395:Sucrose / Q000737:chemistry; D014364:Tryptophan / Q000737:chemistry / Q000235:genetics
chemical_list: D054332:Leishmaniasis Vaccines; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; D050505:Mutant Proteins; D015800:Protozoan Proteins; C090009:kinetoplastid membrane protein 11, Leishmania donovani; D013395:Sucrose; D014364:Tryptophan; D001120:Arginine