Chemo- and Regioselective Lysine Modification on Native Proteins

Journal of the American Chemical Society
Maria J MatosGonçalo J L Bernardes

Abstract

Site-selective chemical conjugation of synthetic molecules to proteins expands their functional and therapeutic capacity. Current protein modification methods, based on synthetic and biochemical technologies, can achieve site selectivity, but these techniques often require extensive sequence engineering or are restricted to the N- or C-terminus. Here we show the computer-assisted design of sulfonyl acrylate reagents for the modification of a single lysine residue on native protein sequences. This feature of the designed sulfonyl acrylates, together with the innate and subtle reactivity differences conferred by the unique local microenvironment surrounding each lysine, contribute to the observed regioselectivity of the reaction. Moreover, this site selectivity was predicted computationally, where the lysine with the lowest p Ka was the kinetically favored residue at slightly basic pH. Chemoselectivity was also observed as the reagent reacted preferentially at lysine, even in those cases when other nucleophilic residues such as cysteine were present. The reaction is fast and proceeds using a single molar equivalent of the sulfonyl acrylate reagent under biocompatible conditions (37 °C, pH 8.0). This technology was demonstrated by...Continue Reading

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Methods Mentioned

BETA
chemical modification
chemical
protein folding
size-exclusion
protein assay
circular dichroism
biolayer interferometry
X-ray
confocal microscopy
flow cytometry

Software Mentioned

MaxEnt
CpHMD

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