Structural significance of hypermodified nucleoside 5-carboxymethylaminomethyluridine (cmnm 5 U) 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 5'-monophosphate (pcmnm5 U) from 'wobble' (34th) position of mitochondrial tRNAs. The energetically preferred pcmnm5 U(34) adopted a 'skew' conformation for C5-substituted side chain (-CH2 -NH2 + -CH2 -COO- ) moiety that orient towards the 5'-ribose-phosphate backbone, which support 'anti' orientation of glycosyl (χ34 ) torsion angle. Preferred conformation of pcmnm5 U(34) was stabilized by O(4) … HC(10), O1P⋯HN(11), O(15) … HN(11), O(15) … HC(10), O4' … HC(6) and O(2) … HC2' hydrogen bonding interactions. The high flexibility of side chain moiety displayed different structural properties for pcmnm5 U(34) . Three different conformations of pcmnm5 U(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 pcmnm5 U(34) . The preferred conformation of pcmnm5 U(34) helps to recognize Guanosine more proficiently than Adenosine from the third position of codons. The role of pcmnm5 U(34) in tRNA biogenesis paves the way to understand its structural significance in usual mitochondrial metabolism and respiration.