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.