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

Abstract

MA’AT analysis 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 3 and 4, and these equations were used in conjunction with experimental spin-couplings to produce unbiased MA’AT models 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’AT analysis 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’AT models indicate a roughly equal distribution of north and south ring conformers of 4 in aqueous (2H2O) solution compared to ∼80% north forms for 3. Librational motion about the mean pseudorotation phase angles P of the preferred north and south conformers of 3 in solution is more constrained than that for 4. The greater rigidity of the β-ribo ring 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’AT analysis 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.

MA’AT: A Web-Based Application to Determine Rotamer Population Distributions in Solution from Nuclear Magnetic Resonance Spin-Coupling Constants

“…No assumptions are made about the CSDs, thereby providing insights into torsional dynamics. MA’AT analysis has been used to study a wide range of conformational properties of saccharides, including O -glycosidic linkage conformations, side-chain conformations, and the pseudorotation of five-membered rings. ,− More recent applications include the modeling of backbone conformation in oligopeptides. In principle, the method should be applicable to any molecule provided that the molecule contains sufficient numbers of redundant J -couplings to interrogate the torsion angle(s) of interest.…”

One-Bond 13C-13C Spin-Coupling Constants in Saccharides: A Comparison of Experimental and Calculated Values By Density Functional Theory Using Solid-State 13C NMR and X-Ray Crystallography

“…Given their high abundance in saccharides and other biomolecules, the inclusion of 1 J CH and 1 J CC values in MA'AT analysis [35][36][37][38][39][40][41] The results of this work point to deficiencies in the ability of DFT, as routinely implemented in this laboratory, to calculate 1 J CC values accurately. The magnitude of the discrepancy between calculated and experimental 1 J CC values depends on how model structures were used in the calculations.…”

“…[2]- [8]) that relate each 1 J CC to a particular torsion angle. The same equations were then used in MA'AT analysis [35][36][37][38][39][40][41] to backcalculate 1 J CC values for comparison to experiment (see Calculations for details).…”

“…X-Ray crystallography and solid-state 13 C NMR spectroscopy have been used synergistically to determine the structural properties of carbohydrates in solution by addressing some of the limitations discussed above. [19][20][21][22][23][24] MA'AT analysis, [35][36][37][38][39][40][41] a new experimental method to model molecular conformation in solution, combines DFT calculations and experimental NMR J-couplings to give probability distributions of molecular torsion angles in solution. MA'AT probability distributions are superimposable on those obtained by MD simulation, allowing direct comparisons of experimental and calculated models.…”

“…MA'AT probability distributions are superimposable on those obtained by MD simulation, allowing direct comparisons of experimental and calculated models. [35][36][37][38][39][40][41] The method uses 2 J and 3 J values primarily to model various conformational elements in saccharides (e.g., O-glycosidic linkages, [35][36][37] ring conformation, 39 side-chain conformation 38,41 ). To extend MA'AT analysis to multi-state models, it would be useful to employ 1 J CC and 1 J CH values as inputs due to their high abundance in saccharides and their attractive conformational properties (e.g., large dynamic ranges).…”