Elucidating the role of ribosomal A1493 in stabilization and rigid support for the codon-anticodon helix from molecular dynamics simulations

TL;DR

This study uses molecular dynamics simulations to reveal how the conserved nucleotide A1493 stabilizes the codon-anticodon helix and enhances decoding accuracy in the ribosome.

Contribution

It uncovers the multifaceted role of A1493 in stabilizing codon-anticodon interactions and provides new mechanistic insights into ribosomal decoding.

Findings

A1493 promotes mRNA-tRNA pairing via entropy-driven stabilization.

A1493 acts as a wedge providing rigid support for the helix.

Steric complementarity is crucial for A1493 flipping and function.

Abstract

The ribosome ensures translational accuracy by monitoring codon-anticodon interactions at the A site decoding center. However, the mechanism by which conserved nucleotide A1493 contributes to this process remains controversial. To address this, we performed molecular dynamics simulations initiated from ribosomal recognition intermediate, revealing A1493's multiple roles in decoding. Through 2D umbrella sampling, we quantified the coupling between A1493 flipping and the stability of the first base pair in the codon-anticodon helix. Our results demonstrate that A1493 promotes mRNA-tRNA pairing through entropy-driven stabilization, amplifies stability differences between cognate and near-cognate tRNAs, and functions as a "wedge" to provide rigid support for the codon-anticodon helix. Further analysis identified steric complementarity as essential for proper A1493 flipping, with the tRNA 37th position playing a key structural role. Additionally, we explored how pseudouridine modification and translocation influence codon-anticodon stability. Together, these findings refine the current mechanistic framework of ribosomal decoding.