Ab Initio Quantum Mechanical Study of the Structures and Energies for the Pseudorotation of 5‘-Dehydroxy Analogues of 2‘-Deoxyribose and Ribose Sugars

Abstract

We have used ab initio quantum mechanical (QM) methods to determine the potential energy of pseudorotation for 3,4-dihydroxy-5-methyl-2-(1-pyrollyl)tetrahydrofuran and 4-hydroxy-5-methyl-2-(1-pyrollyl)-tetrahydrofuran, close analogues of 2′-deoxyribose and ribose sugars. The pyrrole is a substitute for the naturally occurring nucleic acid bases: adenine, thymine, guanine, cytosine, and uracil. At the highest calculation level (LMP2/cc-pVTZ(-f)//HF/6-31G**) for 2′-deoxyribose, we find the C2′-endo conformation is the global minimum. The C3′-endo conformation is a local minimum 0.6 kcal/mol higher in energy, and an eastern barrier of 1.6 kcal/mol separates the two minima. Pseudorotation energies of ribose are quite complex and are strongly affected by local orientations of the 2′ and 3′ hydroxyl groups. When the hydroxyl groups are allowed to assume any conformation, the global minimum remains the C2′-endo conformation. The eastern barrier increases slightly to 1.8 kcal/mol, and the C3′-endo local minimum lies 0.6 kcal/mol above the global minimum. Constraining the torsion angle of the C3′ hydroxyl group to -146°, as is found in RNA polymers, results in the C3′-endo conformation becoming the only energy minimum with a C2′-endo conformation 1.9 kcal/mol higher in energy. Bond angles within the pentofuranose ring are correlated to the pseudorotational phase, as is observed by X-ray crystallography and is predicted by pseudorotation theory. Finally, a force field for use in molecular mechanics and dynamics simulations is presented which reproduces the QM potential energies for the 2′-deoxyribose and ribose sugars.

Chemistry of locked nucleic acids (LNA): Design, synthesis, and bio-physical properties

“…In common for the structures determined, the 2 p -O, 4 t -C methylene bridge of LNA nucleotides is positioned at the brim of the minor groove in duplexes, while the 21 -O, 4 ~ -C methylene bridge of ot-L-LNA nucleotides is positioned at the brim of the major groove. Figure 7), with an energy barrier to interconversion of just "~2 kcal tool -1 [36]. The C2'-endo sugar pucker is the low-energy conformation (~0.6 kcal mo1-1 lower in energy than C3-endo).…”

RNA backbone: Consensus all-angle conformers and modular string nomenclature (an RNA Ontology Consortium contribution)

“…Therefore, we have added a very conservative level of such flexibility to our modeling process, both by allowing small changes from the mean dihedral angles and also by producing a library of riboses optimized with standard bond lengths and specific integer d values across the two ranges of means in Table 1. Each ribose has a pucker phase close either to C39-endo (phase 18°) or to C29-endo (phase 162°), a pucker amplitude between 35°and 40° (Altona and Sundaralingam 1972;Brameld and Goddard 1999), and bond angles close to pucker-specific ideal values (Gelbin et al 1996).…”

Structural Studies of LNA:RNA Duplexes by NMR: Conformations and Implications for RNase H Activity

“…[18,19] In general, Ntype sugars are described by a pseudorotation angle P between À 908 and 908, while for S-type sugars P is between 908 and 2708. [20,21] Due to the low energy barrier between these two conformations (% 2 kcal mol À1 [22,23] ), nucleotides are not trapped completely in either conformation but rather exist in a fast equilibrium between these (the N,S two-state model). [20,21] Recently, we reported sugar conformations of an LNA 9-mer single-stranded deoxyoligonucleotide as well as three 9-and 10-mer LNAs hybridized to unmodified DNA.…”