RT Journal Article
SR Electronic
T1 Atomistic simulations of the <em>E. coli</em> ribosome provide selection criteria for translationally active substrates
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.08.13.503842
DO 10.1101/2022.08.13.503842
A1 Watson, Zoe L.
A1 Knudson, Isaac
A1 Ward, Fred R.
A1 Miller, Scott J.
A1 Cate, Jamie H. D.
A1 Schepartz, Alanna
A1 Abramyan, Ara M.
YR 2022
UL http://biorxiv.org/content/early/2022/08/13/2022.08.13.503842.abstract
AB As genetic code expansion advances beyond L-α-amino acids to backbone modifications and new polymerization chemistries, the field faces an increasingly broad challenge to discover what the ribosome can accommodate. Although the E. coli ribosome tolerates non-L-α-amino acids in vitro, few structural insights are available, and the boundary conditions for efficient bond formation are unknown. We describe a 2.1 Å cryo-EM structure of the E. coli ribosome containing well-resolved α-amino acid monomers coupled with a computational approach for which energy surface minima produced by metadynamics trend in agreement with established incorporation efficiencies. Reactive monomers across diverse structural classes favor a conformational space characterized by an A-site nucleophile to P-site carbonyl distance of &lt; 4 Å and a Bürgi-Dunitz angle of 90-110°. Monomers whose free energy minima fall outside these regions do not react. Application of this model should accelerate the in vivo and in vitro ribosomal synthesis and application of sequence-defined, non-peptide heterooligomers.Competing Interest StatementThe authors have declared no competing interest.