Role of Wybutosine and Mg²⁺ Ions in Modulating the Structure and Function of tRNA^Phe: A Molecular Dynamics Study

Abstract

Transfer RNA remains to be a mysterious molecule of the cell repertoire. With its modified bases and selectivity of codon recognition, it remains to be flexible inside the ribosomal machinery for smooth and hassle-free protein biosynthesis. Structural changes occurring in tRNA due to the presence or absence of wybutosine, with and without Mg2+ ions, have remained a point of interest for structural biologists. Very few studies have come to a conclusion correlating the changes either with the structure and flexibility or with the codon recognition. Considering the above facts, we have implemented molecular modeling methods to address these problems using multiple molecular dynamics (MD) simulations of tRNAPhe along with codons. Our results highlight some of the earlier findings and also shed light on some novel structural and functional aspects. Changes in the stability of tRNAPhe in native or codon-bound states result from the conformations of constituent nucleotides with respect to each other. A smaller change in their conformations leads to structural distortions in the base-pairing geometry and eventually in the ribose-phosphate backbone. MD simulation studies highlight the preference of UUC codons over UUU by tRNAPhe in the presence of wybutosine and Mg2+ ions. This study also suggests that magnesium ions are required by tRNAPhe for proper recognition of UUC/UUU codons during ribosomal interactions with tRNA.

Accelerating the Ensemble Convergence of RNA Hairpin Simulations with a Replica Exchange Structure Reservoir

“…Tetraloop simulations have been performed to identify native states and the underlying folding mechanisms. ,− MD simulations have been used to study various non-coding RNA functions, including binding to target sites as well as interactions with protein complexes . Larger RNA systems have also been simulated, such as tRNA and ribosomes; the effects of ions on tRNA behavior were explored in 2019, and AspRS-tRNA complexes were simulated in 2020 . However, both studies used understandably short (50–100 ns) simulations as significant computational power is required to simulate systems of this size.…”

Magnesium: Biochemistry, Nutrition, Detection, and Social Impact of Diseases Linked to Its Deficiency

“…Later, the importance of Mg 2+ binding for the tRNA tertiary structure has been debated over the years, questioning the prevalent action of nonspecific diffuse binding of Mg 2+ (or other divalent cations) or a specific Mg 2+ interaction [ 2 , 70 , 71 ]. A very recent paper demonstrated that magnesium ions are required by tRNAPhe for proper recognition of UUC/UUU codons during ribosomal interactions with tRNA [ 72 ].…”

Challenges with Simulating Modified RNA: Insights into Role and Reciprocity of Experimental and Computational Approaches

“…Little is known about the structural properties of the tricyclic ring or the accompanying large side chains of these modifications that assist in maintaining the reading frame during translation [ 55 ]. Some molecular modeling studies suggest that restricted conformation sampling induced by the modification and its bulky side chains could be responsible for stabilizing codon–anticodon interactions and indirectly affecting translation [ 56 , 57 ].…”

“…The fully modified X-ray crystal structure of tRNA Phe [ 37 ] and the readily available AMBER parameters for its modified nucleotides from the database maintained by the Bryce Lab [ 68 ] have served as a robust system and act as a foundation for studying how modifications affect overall RNA dynamics. Specifically, studies on tRNA dynamics ([ 87 ] and how individual modifications alter the conformational landscape of the nucleotides to induce localized structural changes [ 57 , 69 , 88 ]) have benefited from this model system.…”