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 tRNALys. Understanding the structural significance of τm5s2U 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′-monophosphate, ‘p-τm5s2U,’ 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-τm5s2U’ has been stabilized by hydrogen bonding interactions between O(11a)…HN(8), O1P(34)…HN(8), O1P(34)…HC(10), O4′(34)…HC(6), S(2)…HC1′(34), O5′(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 tRNALys showed similar conformation as found in RM1 preferred most stable conformation of ‘p-τm5s2U.’ The glycosyl torsion angle of τm5s2U 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 τm5s2U in human mt tRNALys anticodon loop. The MEPs calculations of codon–anticodon models of τm5s2U(34):G3 and τm5s2U(34):A3 showed unique potential tunnels between the hydrogen bond donor and acceptor atoms. These results might be useful to understand the exact role of τm5s2U(34) to recognize AAG/AAA codons and to design new strategies to prevent mitochondrial disease, MERRF.