MA’ATAnalysis of Aldofuranosyl Rings: Unbiased Modeling of Conformational Equilibria and Dynamics in Solution

MA’ATanalysis has been applied to methyl β-d-ribofuranoside (3) and methyl 2-deoxy-β-d-erythro-pentofuranoside (4) to demonstrate the ability of this new experimental method to determine multi-state conformational equilibria in solution. Density functional theory (DFT) was used to obtain parameterized equations for >20 NMR spin-coupling constants sensitive to furanose ring conformation in 3and 4, and these equations were used in conjunction with experimental spin-couplings to produce unbiased MA’ATmodels of ring pseudorotation. These models describe two-state north–south conformational exchange consistent with results obtained from traditional treatments of more limited sets of NMR spin-couplings (e.g., PSEUROT). While PSEUROT, MA’AT, and aqueous molecular dynamics models yielded similar two-state models, MA’ATanalysis gives more reliable results since significantly more experimental observables are employed compared to PSEUROT, and no assumptions are needed to render the fitting tractable. MA’ATmodels indicate a roughly equal distribution of north and south ring conformers of 4in aqueous (2H2O) solution compared to ∼80% north forms for 3. Librational motion about the mean pseudorotation phase angles Pof the preferred north and south conformers of 3in solution is more constrained than that for 4. The greater rigidity of the β-riboring may be caused by synergistic stereoelectronic effects and/or noncovalent (e.g., hydrogen-bonding) interactions in solution that preferentially stabilize north forms of 3. MA’ATanalysis of oligonucleotides and other furanose ring-containing biomolecules promises to improve current experimental models of sugar ring behavior in solution and help reveal context effects on ring conformation in more complex biologically important systems.