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Lysine‐specific peptide and protein modification strategies are widely used to study charge‐related functions and applications. However, these strategies often result in the loss of the positive charge on lysine, significantly impacting the charge‐related properties of proteins. Herein, we report a strategy to preserve the positive charge and selectively convert amines in lysine side chains to amidines using nitriles and hydroxylamine under aqueous conditions. Various unprotected peptides and proteins were successfully modified with a high conversion rate. Moreover, the reactive amidine moiety and derived modification site enable subsequent secondary modifications. Notably, positive charges were retained during the modification. Therefore, positive charge‐related protein properties, such as liquid‐liquid phase separation behaviour of α‐synuclein, were not affected. This strategy was subsequently applied to a lysine rich protein to develop an amidine‐containing coacervate DNA complex with outstanding mechanical properties. Overall, our innovative strategy provides a new avenue to explore the characteristics of positively charged proteins. [ABSTRACT FROM AUTHOR]

Liquid–liquid phase separation (LLPS) was recently discovered to be a ubiquitous method of substance organization in living organisms, which plays an important regulatory role in various life processes and can also be closely associated with the development of many diseases. Glycation is one of the most important non-enzymatic post-translational modifications (PTMs), which accumulates in vivo gradually with life processes and affects the properties and functions of proteins. Here, we investigated the effect of glycation on LLPS and explored the molecular mechanisms behind it. We found that glycation reduces electrostatic interactions and increases hydrophobic interactions, and consequently affects LLPS. [ABSTRACT FROM AUTHOR]

Considering the fact that site‐selective late‐stage diversification of peptides and proteins remains a challenge for biochemistry, strategies targeting low‐abundance natural amino acids need to be further developed. As an extremely oxidation‐sensitive and low‐abundance amino acid, methionine emerges as a promising target for chemo‐ and site‐selective modification. Herein we report an efficient and highly selective modification on methionine residues by one‐pot O‐ and N‐transfer reaction, generating sulfoximine‐modified peptides with near‐perfect conversion within 10 min. Moreover, the great tolerance to other natural amino acids has been demonstrated in reactions with various peptide substrates. To demonstrate the generality of this protocol, we have modified natural peptides and obtained sulfoximination products with high conversion rates. This methodology provides a novel strategy as the expansion of the methionine‐based peptide functionalization toolbox. [ABSTRACT FROM AUTHOR]

Chemical protein modifications facilitate the investigation of natural posttranslational protein modifications and allow the design of proteins with new functions. Proteins can be modified at a late stage on amino acid side chains by chemical methods. The indole moiety of tryptophan residues is an emerging target of such chemical modification strategies because of its unique reactivity and low abundance. This review provides an overview of the recently developed methods of tryptophan modification at the peptide and protein levels. [ABSTRACT FROM AUTHOR]