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Structural significance of conformational preferences and ribose ring puckering of newly discovered hyper modified nucleotide, 5'-monophosphate 2-methylthio cyclic N 6 -threonylcarbamoyladenosine (p-ms 2 ct 6 A) have been investigated using quantum chemical semi-empirical RM1 and molecular dynamics simulation techniques. Automated geometry optimization of most stable structure of p-ms 2 ct 6 A has also been carried out with the help of abinitio (HF SCF, DFT) as well as semi empirical quantum chemical (RM1, AM1, PM3, and PM6) methods. Most stable structure of p-ms 2 ct 6 A is stabilized by intramolecular interactions between N(3)…HC(2'), N(1)…HC(16), O(13)…HC(15), and O(13)…HO(14). The torsion angles alpha (α) and beta (β) show the significant characteristic patterns with the involvement of intramolecular hydrogen bonding to provide stability to the p-ms 2 ct 6 A. Further, molecular dynamics simulations of p-ms 2 ct 6 A revealed the role of ribose sugar ring puckering i.e. C2'-endo and C3'-endo on the structural dynamics of ms 2 ct 6 A side chain. The modified nucleotide p-ms 2 ct 6 A periodically prefers both the C2'-endo and C3'-endo sugar with 'anti' and 'syn' conformations. This property of p-ms 2 ct 6 A could be useful to recognize the starting ANN codons. All atom explicit MD simulation of anticodon loop (ACL) of tRNA Lys of Bacillus subtilis containing ms 2 ct 6 A at 37th position showed the U-turn feature, base stacking ability with other adjacent bases and hydrogen bonding interactions similar to the isolated base p-ms 2 ct 6 A. The ribose sugar puckering contributes to the orientation of the side chain conformation of p-ms 2 ct 6 A. Thus, the present study could be helpful to understand the structure-function relationship of the hypermodified nucleoside, ms 2 ct 6 A in recognition of the proper codons AAA/AAG during protein biosynthesis., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Hypermodified bases present at 3'-adjacent (37 th ) position in anticodon loop of tRNA Phe are well known for their contribution in modulating codon-anticodon interactions. Peroxywybutosine (o2yW), a wyosine family member, is one of such tricyclic modified bases observed at the 37 th position in tRNA Phe . Conformational preferences and three-dimensional structural analysis of peroxywybutosine have not been investigated in detail at atomic level. Hence, in the present study quantum chemical semi-empirical RM1 and multiple molecular dynamics (MD) simulations have been used to study structural significance of peroxywybutosine in tRNA Phe . Full geometry optimizations over the peroxywybutosine base have also been performed using ab-initio HF-SCF (6-31G**), DFT (B3LYP/6-31G**) and semi-empirical PM6 method to compare the salient properties. RM1 predicted most stable structure shows that the amino-carboxy-propyl side chain of o2yW remains 'distal' to the five membered imidazole ring of tricyclic guanosine. MD simulation trajectory of the isolated peroxy base showed restricted periodical fluctuations of peroxywybutosine side chain which might be helpful to maintain proper anticodon loop structure and mRNA reading frame during protein biosynthesis process. Another comparative MD simulation study of the anticodon stem loop with codon UUC showed various properties, which justify the functional implications of peroxywybutosine at 37 th position along with other modified bases present in ASL of tRNA Phe . Thus, this study presents an atomic view into the structural properties of peroxywybutosine, which can be useful to determine its role in the anticodon stem loop in context of codon-anticodon interactions and frame shift mutations., (Copyright © 2017 Elsevier B.V. All rights reserved.)