Molecular Dynamics Simulations Suggest a Non-Doublet Decoding Model of -1 Frameshifting by tRNA^Ser3

In-frame decoding in the ribosome occurs through canonical or wobble Watson-Crick pairing of three mRNA codon bases (a triplet) with a triplet of anticodon bases in tRNA. Departures from the triplet-triplet interaction can result in frameshifting, meaning downstream mRNA codons are then read in a different register. There are many mechanisms to induce frameshifting, and most are insufficiently understood. One previously proposed mechanism is doublet decoding, in which only codon bases 1 and 2 are read by anticodon bases 34 and 35, which would lead to -1 frameshifting. In E. coli, tRNA^Ser3_GCU can induce -1 frameshifting at alanine (GCA) codons. The logic of the doublet decoding model is that the Ala codon's GC could pair with the tRNA^Ser3's GC, leaving the third anticodon residue U36 making no interactions with mRNA. Under that model, a U36C mutation would still induce -1 frameshifting, but experiments refute this. We perform all-atom simulations of wild-type tRNA^Ser3, as well as a U36C mutant. Our simulations revealed a hydrogen bond between U36 of the anticodon and G1 of the codon. The U36C mutant cannot make this interaction, as it lacks the hydrogen-bond-donating H3. The simulation thus suggests a novel, non-doublet decoding mechanism for -1 frameshifting by tRNA^Ser3 at Ala codons.