Research Topic

Chemical Ligation Tools for Protein Engineering

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Chemistry has always played an important role in the study of biological processes. Proteins have been a major focus of biological chemistry research, both from the perspective of fully understanding their innate biological functions and from the perspective of harnessing those functions for a variety of ...

Chemistry has always played an important role in the study of biological processes. Proteins have been a major focus of biological chemistry research, both from the perspective of fully understanding their innate biological functions and from the perspective of harnessing those functions for a variety of applications. Today, the study of proteins is even more important because of the many successful genome-sequencing projects that have revealed hundreds of thousands of new proteins as predicted from sequence data. Numerous scientific studies require access to chemically modified proteins. Some of these molecules, however, are impossible to prepare using standard DNA recombinant techniques. This is mostly due to the intrinsic limitations of the genetic code, which only tolerates the introduction of 20 naturally occurring amino acids. Chemical synthesis, on the other hand, allows the incorporation of non-natural amino acids in addition to posttranslational modifications.
The use of peptide chemical ligation tools has emerged as a promising method for the total synthesis and semisynthesis of proteins. Chemical ligation uses efficient reactions between unprotected peptides to form a stable peptide bond in a chemoselective way between the alpha-carboxyl group of one of the peptide fragments and the alpha-amino group of the other peptide fragment. This method was developed to solve the intrinsic problems associated with the historical approach for polypeptide synthesis employing fragment condensation of large, protected polypeptide building blocks.

A defining point in chemical synthesis of proteins occurred when native chemical ligation (NCL) was first introduced in 1994. In this reaction two unprotected peptides, one containing a C-terminal alpha-thioester group and the other an N-terminal Cys, react chemoselectively under neutral conditions to form a native peptide bond at the ligation site. The NCL approach has been further extended to allow the semisynthesis of proteins from recombinant and synthetic fragments. This approach termed expressed protein ligation (EPL) extends the size and complexity of the protein targets available to chemical engineering.

This Frontiers Research Topic brings together leading scientists making use of chemical ligation tools for the production of chemically engineered proteins to study protein structure and biological function.

Areas to be covered in this Research Topic may include, but are not limited to:

• Chemical ligation techniques beyond NCL and EPL (e.g. traceless ligation techniques, desulfurization approaches, etc)
• Synthetic methods for the production C-terminal alpha-thioester polypeptides
• Use of protein splicing tools for ligation of polypeptides
• Segmental isotopic labeling of proteins for studying protein structure and function (e.g. NMR, EPR, IR, etc)
• Production of constrained (backbone) cyclized polypeptides
• Production of membrane proteins
• Chemical ligation tools for protein immobilization and site-specific labeling of proteins
• Production of Se-containing proteins
• Introduction of post-translational modifications into proteins to study structure and biological function (e.g. histone modification)


Keywords: protein engineering, chemical ligation, chemical tools, native chemical ligation, expressed protein logation


Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

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