Structural significance of modified nucleoside 5-taurinomethyl-2-thiouridine, τm5s2U, found at ‘wobble’ position in anticodon loop of human mitochondrial tRNALys

Abstract

The myoclonus epilepsy associated with ragged-red fibers (MERRF) is a mitochondrial encephalomyopathic disease caused due to the lack of hypermodified nucleoside 5-taurinomethyl-2-thiouridine at 'wobble' 34th position in the anticodon loop of human mitochondrial tRNA Lys . Understanding the structural significance of sm 5 s 2 U might be helpful to get more information about the MERRF disease in detail at the atomic level. Hence, conformational preferences of hypermodified nucleoside 5-taurinomethyl-2-thiouridine 5 0 -monophosphate, 'p-sm 5 s 2 U,' have been studied using semiempirical quantum chemical RM1 method. Full geometry optimization using ab initio molecular orbital HF-SCF (6-31G**) and DFT (B3LYP/6-31G**) methods has also been used to compare the salient features. The RM1 preferred most stable conformation of 'p-sm 5 s 2 U' has been stabilized by hydrogen bonding interactions between O(11a)…HN (8), O1P (34) … HN(8), O1P (34) …HC(10), O4 0 (34) …HC(6), S(2)…HC1 0 (34), O5 0 (34) …HC(6), and O(4)…HC (7). Another conformational study of 5-taurinomethyl-2-thiouridine side chain in the presence of anticodon loop bases of human mitochondrial tRNA Lys showed similar conformation as found in RM1 preferred most stable conformation of 'p-sm 5 s 2 U.' The glycosyl torsion angle of sm 5 s 2 U retains 'anti' conformation. Similarly, MD simulation results are also found in accordance with RM1 preferred stable structure. The solvent-accessible surface area calculations revealed surface accessibility of sm 5 s 2 U in human mt tRNA Lys anticodon loop. The MEPs calculations of codon-anticodon models of sm 5 s 2 U (34) :G 3 and sm 5 s 2 U (34) :A 3 showed unique potential tunnels between the hydrogen bond donor and acceptor atoms. These results might be useful to understand the exact role of sm 5 s 2 U (34) to recognize AAG/ AAA codons and to design new strategies to prevent mitochondrial disease, MERRF.

Idiosyncratic recognition of UUG/UUA codons by modified nucleoside 5-taurinomethyluridine, τm5U present at ‘wobble’ position in anticodon loop of tRNALeu: A molecular modeling approach

“…In the context of ASL tRNA Leu , it has been observed that τm 5 U 34 side chain also interacts with the ribose ring of U 33 viz . O2' 33 …HN(8) 34 ( Fig 2E ) and O3' 33 …HN(8) 34 ( Fig 2F ), which could be helpful to maintain ‘anti’ conformation of glycosyl torsion angle as found in previous studies [ 13 – 14 ]. These hydrogen bonding interactions might be useful to retain the proper orientation of τm 5 U 34 side chain.…”

“…The hydrogen bonding interaction, O4' 34 …HC(6) 34 (Fig 2A) between ribose ring and τm 5 U 34 base has been found stable throughout MD simulation, whereas the interaction, O5' 34 …HC(6) 34 (Fig 2B) was found disturbed. These interactions might help to maintain the ‘anti’ conformation of glycosyl torsion angle ‘χ’, as found in earlier studies [13–14]. The hydrogen bonding interaction, O1P 34 …HC(10) 34 (Fig 2C) between phosphate backbone and τm 5 U 34 side chain assists to retain ‘anti’ conformation of glycosyl torsion angle.…”

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

“…Thus, the D-loop is involved in stabilization of the 3D structure of the tRNA molecule. The D-loop structure is also essential for recognition of the tRNA molecule by aminoacyl tRNA synthetases. , Similarly, the importance of the anticodon loop and anticodon stem loop has been well documented in previous reports. , Hence, the stability of these component domains was individually assessed to check for local structural changes with the help of parameters such as the RMSD or structural visualization.…”

“…42,43 Similarly, the importance of the anticodon loop and anticodon stem loop has been well documented in previous reports. 13,17 Hence, the stability of these component domains was individually assessed to check for local structural changes with the help of parameters such as the RMSD or structural visualization.…”

“…tRNA is unique in its base composition as it encompasses a variety of modified nucleic acid bases in addition to the usual RNA bases, A, U, G, and C . Various studies have reported that these modified bases are crucial elements contributing to various properties of the molecule. − Some studies also show that the absence of a specific modified nucleoside in tRNA causes structural deformities, which in turn cause considerable damage to native functions of the molecule. − …”