The templated synthesis of proteins containing non-canonical and expanded backbone monomers (collectively called nnAAs) promises to vastly expand the chemical space available to biological therapeutics and materials, but existing technologies remain limiting. Addressing these limitations requires a deeper understanding of how the translational mechanism is perturbed (or not) by nnAAs.
In a recent paper in ACS Central Science, a team from the Blanchard, Miller, and Schepartz labs examined the impact of the non-canonical ⍺-amino acid para-azido-phenylalanine (pAzF) as well as D-Phe and the (R) and (S) enantiomers of ꞵ2– and ꞵ3-Phe on the utilization of acylated tRNAs by the central translation factor EF-Tu. With the exception of pAzF, all nnAAs tested disrupted acyl-tRNA binding of EF-Tu by at least one order of magnitude, and the ribosome-bound acyl-tRNAs were utilized inefficiently by the ribosome. They conclude that if the goal is a sequence-defined polymers containing even a single ꞵ2– or ꞵ3-amino acid, the role of EF-Tu and the efficiency and stability of ternary complex formation cannot be ignored.
Check out the paper: https://pubs.acs.org/doi/10.1021/acscentsci.4c00314