Description of chemical modification of proteins

Chemical modification of proteins is an important tool for exploring natural systems, creating therapeutic conjugates and generating novel protein constructs. Site-selective reactions require precise control of chemical and regional selectivity under environmental and aqueous conditions. There are now multiple approaches to achieving selective modification of natural and non-natural amino acids — each with advantages and limitations — providing a “toolkit” that, until 20 years ago, was largely limited to reactions with nucleophilic cysteine and lysine residues. Applied in a biologically benign way, this chemistry could form the basis of true synthetic biology.

Protein modifications occur widely in nature, increasing the diversity of protein structures and thus increasing function by up to two orders of magnitude. However, our ability to synthesize the ability to mimic nature’s ability to install such modifications is largely limited by the chemicals available. Reactions at a single amino acid or site between a large number of active carboxylic acids, amides, amines, alcohols, and mercaptans present a significant and exciting challenge in terms of both chemistry and regional selectivity. The underlying transformations, if they are related, are shaped by the need for biological environmental conditions (i.e. <37 °C, pH 6-8, water-based solvents) so as not to disrupt protein structure and/or function. Ideally, this should be transformed almost completely to produce homogeneous builds 2, 3, and 4. Modified proteins have many applications; They vary as much as the in vivo tracing-5 of protein-fluorophore conjugates to the polyethylene glycol (PEG) ylation of therapeutic proteins to reduce immunogenicity, from the production of materials with novel properties 7 to the exploration of mechanisms of pathological enzymes.

While there have been many examples in the past of so-called “biological integration” (even by dedicated journals), those that teach strong strategic courses are rarer still. The rigor of chemical methods, including proper characterization, has been lacking — and may be replaced by a pragmatic desire for useful products. In an age that now craves precise molecular knowledge of protein function, previously rare (historically) examples of precise protein chemistry become critical.

We (subjectively) thought we could find a groundbreaking example in the work of Wilchek9 and later Bender10 and Koshland11. They chemically convert serine to cysteine as an early example of site-directed protein mutagenesis that, we believe, is still not well understood. It laid the foundation for methods that are now producing results in a way that is only now widely used. In the post-genomic era, more familiar with the limitations of the “gene-only” approach, this may prove uniquely powerful.

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