Abstract
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, tRNASer3GCU 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 tRNASer3′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 tRNASer3, 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 tRNASer3 at Ala codons.
Highlights
In the ribosome, messenger RNA is most often decoded by reading in three-base steps, by cognate transfer RNAs, until a stop codon is encountered
The ribosome is a challenging system to model by molecular dynamics (MD), due to its very large size and extensive conformational changes occurring over long time scales
MD simulations typically run over time scales of weeks or even months, and iteration is typically needed leading to considerable cost in labor, calendar, and computer time
Summary
Messenger RNA (mRNA) is most often decoded by reading in three-base (codon) steps, by cognate transfer RNAs (tRNAs), until a stop codon is encountered. Frameshifting, misincorporation, premature termination, and stop-codon read-through [1] occur This can be part of natural regulatory processes, and are heavily used by viruses [2]; they can play a role in tumorigenesis [3]. They occur at low frequency, apparently as errors. Structures of the ribosome showing cognate and near-cognate interactions [4,5] have given us considerable understanding of decoding. −1 frameshifting remains difficult to characterize by experimental structural biology
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