Structural significance of hypermodified nucleic acid base hydroxywybutine (OHyW) which occur at 37th position in the anticodon loop of yeast tRNA(Phe).

Conformational preferences of hypermodified nucleic acid base hydroxywybutine (OHyW) have been studied using quantum chemical single point semi-empirical PM3 method. Automated geometry optimization using semi-empirical RM1, molecular mechanics force field (MMFF) along with ab-initio HF-SCF (6-31G** basis set) and DFT (B3LYP/6-31G** basis set) calculations have also been made to compare the salient features. Molecular electrostatic potentials (MEPs) depict the polarities of hydroxywybutine (OHyW) side chain. Another conformational study showed that hydroxywybutosine side chain interacts with adjacent bases within the anticodon loop of tRNA(Phe). The solvent accessible surface area (SASA) calculations revealed the structural role of hydroxywybutine in anticodon loop. Explicit molecular dynamics (MD) simulation has been done over the PM3 most stable structure of OHyW. The hydroxywybutine side chain prefers 'distal' conformation i.e. spreads away from the cyclic five membered imidazole moiety of modified tricyclic guanine base. The predicted preferred conformation of hydroxywybutine may prevent extended Watson-Crick base pairing during protein biosynthesis process. This conformation of OHyW stabilized by intramolecular interactions between O(6)⋯HO(16), O(6)⋯HC(15) and O(20)⋯HC(17). Further stabilization is also expected from interactions between O(22)⋯HC(16) and O(23)⋯HC(15). Explicit molecular dynamics (MD) simulation over the PM3 most stable structure of OHyW support the preferred geometry by preserving the 'distal' orientation of hydroxywybutine side chain and intramolecular hydrogen bonding interactions. MD simulation study revealed the role of hydroxyl group of OHyW to avoid fluctuations and prevent multiple iso-energetic conformations of hydroxywybutine side chain as compared to wybutine (yW).