Comparative Structural Dynamics of tRNAPhe with Respect to Hinge Region Methylated Guanosine: A Computational Approach

Abstract

Transfer RNAs (tRNAs) contain various uniquely modified nucleosides thought to be useful for maintaining the structural stability of tRNAs. However, their significance for upholding the tRNA structure has not been investigated in detail at the atomic level. In this study, molecular dynamic simulations have been performed to assess the effects of methylated nucleic acid bases, N (2)-methylguanosine (m(2)G) and N (2)-N (2)-dimethylguanosine (m 2 (2) G) at position 26, i.e., the hinge region of E. coli tRNA(Phe) on its structure and dynamics. The results revealed that tRNA(Phe) having unmodified guanosine in the hinge region (G26) shows structural rearrangement in the core of the molecule, resulting in lack of base stacking interactions, U-turn feature of the anticodon loop, and TΨC loop. We show that in the presence of the unmodified guanosine, the overall fold of tRNA(Phe) is essentially not the same as that of m(2)G26 and m 2 (2) G26 containing tRNA(Phe). This structural rearrangement arises due to intrinsic factors associated with the weak hydrogen-bonding patterns observed in the base triples of the tRNA(Phe) molecule. The m(2)G26 and m 2 (2) G26 containing tRNA(Phe) retain proper three-dimensional fold through tertiary interactions. Single-point energy and molecular electrostatics potential calculation studies confirmed the structural significance of tRNAs containing m(2)G26 and m 2 (2) G26 compared to tRNA with normal G26, showing that the mono-methylated (m(2)G26) and dimethylated (m 2 (2) G26) modifications are required to provide structural stability not only in the hinge region but also in the other parts of tRNA(Phe). Thus, the present study allows us to better understand the effects of modified nucleosides and ionic environment on tRNA folding.

Structure and Dynamics of tRNAMet Containing Core Substitutions

“…An increase in flexibility was expected in the tRNA loops and at the AS compared to the helical regions based on previous MD studies of yeast tRNA Met and E. coli tRNA Phe . 14 , 15 This was also observed for the WT tRNA Met ( Figure 3 ).…”

“…Compared to the other tRNAs previously studied, an increase to 10 Å is a significant increase. 14 , 15 From residues 17–20, the G18A substitution directly affects the local environment, where the other two variants more closely resemble that of the WT tRNA. In the AC region, all four configurations have a peak centered about the CAU AC, although G19A exhibits a less AC fluctuation.…”

One‐carbon metabolism, folate, zinc and translation

“…It may be required for import of tRNA into mitochondria (Paris and Alfonzo, 2018). Finally, a double methylation of base m 2 2 G26 and also probably G27 corresponding to the generally unmethylated hinge region of E. coli tRNA Phe stablilizes the region in Aquifex or Pyrococcus families (Awai et al , 2009; Sonawane et al , 2016).…”

“…It may be required for import of tRNA into mitochondria (Paris and Alfonzo, 2018). Finally, a double methylation of base m 2 2 G26 and also probably G27 corresponding to the generally unmethylated hinge region of E. coli tRNA Phe stablilizes the region in Aquifex or Pyrococcus families (Awai et al, 2009;Sonawane et al, 2016). 1-C-dependent modifications of the anticodon Modifications of the anticodon, often derived directly from 1-C metabolism, have a critical role in the maintenance of translation accuracy and stability of the anticodon against RNases (Sokolowski et al, 2018).…”

The mammalian mitochondrial epitranscriptome

“…The dimethylation to form m 2 2 G26 was one of the first RNA modifications to be identified [136] and blocks base pairing with cytosine residues and so may function in a similar manner to m 1 A9 by interfering with unfavourable interactions [137]. A recent computational approach has demonstrated a decreased structural stability upon the loss of m 2 G or m 2 2 G [138], moreover human cells deficient in TRMT1 activity display perturbed mitochondrial translation and hypersensitivity to oxidising agents [135]. Large scale structural rearrangements can also be induced through modifications that do not alter base pairing.…”