Exploring and Expanding the Protein Universe with Non-Canonical Amino Acids

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Background

The site-specific incorporation of unnatural or non-canonical amino acids (ncAAs) into proteins is a universally important tool for systems bioengineering at the interface of chemistry, biology, and biotechnology. The synergistic use of ncAA and related technologies (e.g. Xeno nucleic acids) should enable:
i) New opportunities to manipulate, design and elucidate protein structure, dynamics, and function.
ii) A deeper understanding of natural and evolved translational systems and their importance for artificial biology.
iii) The synthesis of novel biopolymers, creating a solid basis for synthetic cells, which is also an important technology in the production of new classes of medically relevant protein-based scaffolds.
Research on reprogrammed protein translation has now reached an experimental and intellectual maturity: more than 200 ncAA (i.e. more than ten times larger variety than standard amino acids) have been introduced into proteins using different routes: genetic code expansion (GCE), selective pressure incorporation (SPI), chemical mutagenesis, protein semi-synthesis, and peptide synthesis.

Although the field is almost 30-year-old, has become terminologically established, and is methodologically broad, there is still a strong need to overcome the bottlenecks of traditional approaches to producing high-quality chemically modified polypeptides. The majority of ncAAs in practice are the chemical variants of amino acid side-chains while there are very few studies with basic building blocks having alternative backbones (inverted chirality, chemical modifications of the alpha-carbon atom, etc.) There is also a lack of systematic research on the biological consequences of ncAA incorporation and the molecular mechanism that determine the effectiveness of orthogonal translation. Therefore, we believe that future developments in the ncAA field must involve:
(a) Protein engineering, including rational design and directed evolution assisted by artificial intelligence.
(b) Reprogrammed protein translation with orthogonal sense codon reassignment.
(c) Metabolic engineering, including cofactor engineering.
(d) Adaptive laboratory evolution and genome engineering/editing, for codon reassignment with the option of integrating expanded genetic alphabets to create synthetic cells with altered genetic codes. The long-term mission should be to convert the expansion of the genetic code/genetic code engineering into a routine method for every laboratory and every industry.

On a more practical level, this Research Topic is based on 3 basic pillars: (i) genetic code engineering as an approach, tool, and technology for life sciences, (ii) a broad range of applications of ncAAs, (iii) an active approach to synthetic cells (life). Specific themes include but are not limited to:
● Integrative/hybrid approaches to incorporate ncAA (e.g. GCE-SPI)
● Novel applications of ncAA in any area (bio-orthogonal chemistry, drug discovery, etc.)
● Augmenting the ncAA chemical space to cover new side-chains and backbones (e.g. D-aa)
● Robust procedures to site-specifically install multiple (>2) ncAA
● Methods to incorporate ncAA in multiple proteins or even whole proteomes

We encourage submissions from both “developers” of these technologies as well as “users”. In silico, in vitro, and in vivo studies are all welcome. Regular papers, short communications, or reviews are equally acceptable.

Dr. Kensaku Sakamoto receives funding from a company relating to the subject of this Research Topic

Keywords: Non-Standard Amino Acids, Protein Structure, Protein Dynamics, Protein Functions, Structure-Function, Protein Engineering

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