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Desolvation of Peptide Bond by O to S Substitution Impacts Protein Stability

Khatri, B and Raghunathan, S and Chakraborti, S and Rahisuddin, R and Kumaran, S and Tadala, R and Wagh, P and Priyakumar, UD and Chatterjee, J (2021) Desolvation of Peptide Bond by O to S Substitution Impacts Protein Stability. In: Angewandte Chemie - International Edition .

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Official URL: https://doi.org/10.1002/anie.202110978


Amino acid side chains are key to fine-tuning the microenvironment polarity in proteins composed of polar amide bonds. Here, we report that substituting an oxygen atom of the backbone amide bond with sulfur atom desolvates the thioamide bond, thereby increasing its lipophilicity. The impact of such local desolvation by O to S substitution in proteins was tested by synthesizing thioamidated variants of Pin1 WW domain. We observe that a thioamide acts in synergy with nonpolar amino acid side chains to reduce the microenvironment polarity and increase protein stability by more than 14 °C. Through favorable van der Waals and hydrogen bonding interactions, this single atom substitution significantly stabilizes proteins without altering the amino acid sequence and structure of the native protein. © 2021 Wiley-VCH GmbH

Item Type: Journal Article
Publication: Angewandte Chemie - International Edition
Publisher: John Wiley and Sons Inc
Additional Information: The copyright for this article belongs to John Wiley and Sons Inc
Keywords: Amides; Amino acids; Atoms; Biosynthesis; Hydrogen bonds; Van der Waals forces, Amide bond; Amino-acids; Desolvation; Isostere; Microenvironments; Peptide bonds; Protein stability; Proteomimetics; Side-chains; Thioamides, Proteins
Department/Centre: Division of Biological Sciences > Molecular Biophysics Unit
Date Deposited: 28 Nov 2021 06:26
Last Modified: 28 Nov 2021 06:26
URI: http://eprints.iisc.ac.in/id/eprint/70445

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