Structural significance of hypermodified nucleoside 5-carboxymethylaminomethyluridine (cmnm5U) from ‘wobble’ (34th) position of mitochondrial tRNAs: Molecular modeling and Markov state model studies

A quantum chemical semi-empirical RM1 approach was used to deduce the structural role of hypermodified nucleoside 5-carboxymethylaminomethyluridine 5ʹ-monophosphate (pcmnm5U) from ‘wobble’ (34th) position of mitochondrial tRNAs. The energetically preferred pcmnm5U(34) adopted a ‘skew’ conformation for C5-substituted side chain (-CH2-NH2+-CH2-COO-) moiety that orient towards the 5ʹ-ribose-phosphate backbone, which support ‘anti’ orientation of glycosyl (χ34) torsion angle. Preferred conformation of pcmnm5U(34) was stabilized by O(4) … HC(10), O1P⋯HN(11), O(15) … HN(11), O(15) … HC(10), O4ʹ … HC(6) and O(2) … HC2ʹ hydrogen bonding interactions. The high flexibility of side chain moiety displayed different structural properties for pcmnm5U(34). Three different conformations of pcmnm5U(34) were observed in molecular dynamics simulations and Markov state model studies. The unmodified uracil revealed ‘syn’ and ‘anti’ orientations for glycosyl (χ34) torsion angle that substantiate the role of “-CH2-NH2+-CH2-COO-” moiety in maintaining the ‘anti’ orientation of pcmnm5U(34). The preferred conformation of pcmnm5U(34) helps to recognize Guanosine more proficiently than Adenosine from the third position of codons. The role of pcmnm5U(34) in tRNA biogenesis paves the way to understand its structural significance in usual mitochondrial metabolism and respiration. [Display omitted] •The RM1 preferred “skew” conformation of pcmnm5U(34) orient towards 5ʹ-ribose-phosphate backbone.•MD simulations and MSM analysis showed three different conformations for pcmnm5U(34).•The ‘syn’ and ‘anti’ orientations of uracil substantiate the role of “-CH2-NH2+-CH2-COO-” moiety in the stability of pcmnm5U(34).•Preferred pcmnm5U(34) recognizes Guanosine more proficiently than Adenosine from the third position of codons.