Abstract
Compounds including non-canonical amino acids (ncAAs) or other artificially designed molecules can find a lot of applications in medicine, industry and biotechnology. They can be produced thanks to the modification or extension of the standard genetic code (SGC). Such peptides or proteins including the ncAAs can be constantly delivered in a stable way by organisms with the customized genetic code. Among several methods of engineering the code, using non-canonical base pairs is especially promising, because it enables generating many new codons, which can be used to encode any new amino acid. Since even one pair of new bases can extend the SGC up to 216 codons generated by a six-letter nucleotide alphabet, the extension of the SGC can be achieved in many ways. Here, we proposed a stepwise procedure of the SGC extension with one pair of non-canonical bases to minimize the consequences of point mutations. We reported relationships between codons in the framework of graph theory. All 216 codons were represented as nodes of the graph, whereas its edges were induced by all possible single nucleotide mutations occurring between codons. Therefore, every set of canonical and newly added codons induces a specific subgraph. We characterized the properties of the induced subgraphs generated by selected sets of codons. Thanks to that, we were able to describe a procedure for incremental addition of the set of meaningful codons up to the full coding system consisting of three pairs of bases. The procedure of gradual extension of the SGC makes the whole system robust to changing genetic information due to mutations and is compatible with the views assuming that codons and amino acids were added successively to the primordial SGC, which evolved minimizing harmful consequences of mutations or mistranslations of encoded proteins.
Highlights
The basic diversity of proteins fulfilling a wide range of functions within organisms is based on 20 naturally occurring amino acids.royalsocietypublishing.org/journal/rsos R
Following the properties of the graph G, we formulate some characteristics, which are useful in describing the properties of the subgraph G[Vn], 1 ≤ n ≤ 96 induced by the set of codons Vn and at the same time in developing the optimal extended genetic code (EGC)
The huge number of combinations of non-canonical and canonical bases in the creation of new codon groups means that the genetic code can be extended in various ways
Summary
The basic diversity of proteins fulfilling a wide range of functions within organisms is based on 20 naturally occurring amino acids.royalsocietypublishing.org/journal/rsos R. The proteins are modified post-translationally, which extends their properties It is 2 tempting to increase this variety with artificially designed amino acids or other molecules. The first approach uses stop translation codons (e.g. rarely used UAG) to encode ncAAs [2,3,4,5]. This method requires a modified aminoacyl-tRNA synthetase which charges a tRNA with an ncAA. This suppressor tRNA must recognize the stop codon and ncAA is incorporated into a protein during its synthesis. This method enables utilization of up to two stop codons because one of the three codons must be left as a termination signal of translation [6]
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