MA'AT Analysis: Probability Distributions of Molecular Torsion Angles in Solution from NMR Spectroscopy

Conspectus Monosaccharides adopt multipleconformationsin solution, and thisstructural complexity increases significantly when they are assembledinto oligosaccharides and polysaccharides. Characterization of theconformational properties of saccharides in solution by NMR spectroscopyhas been hampered by several complicating factors, including difficultyinterpreting spectra because of significant signal overlap, populationaveraging of NMR parameters, and unique properties of the spectrathat make accurate measurements of NMR parameters prone to error (e.g.,non-first-order effects on J-couplings). Currentconformational assignments rely heavily on theoretical calculations,especially molecular dynamics (MD) simulations, to interpret the experimentalNMR parameters. While these studies assert that the available experimentaldata fit the calculated models well, a lack of independent experimentalvalidation of the force fields from which MD models are derived andan inability to test all possible models that might be compatiblewith the experimental data in an unbiased manner make the approachless than ideal. NMR spin couplings or J-couplingshave been usedas structure constraints in organic and other types of molecules formore than six decades. The dihedral angle dependence of vicinal (three-bond) H-1-H-1 spin couplings ((3) J (HH)) first described by Karplus led to an explosionof applications for a wide range of conformational problems. Othervicinal J-couplings (e.g., (3) J (CCOP), (3) J (HCOP), and (3) J (COCH)) have been found to exhibitsimilar dihedral angle dependencies. (3) J values have been used to assign the preferred conformation in moleculesthat are conformationally homogeneous. However, many molecules, particularlythose in biological systems, are conformationally flexible, whichcomplicates structural interpretations of J valuesin solution. Three-state staggered models are often assumed in orderto deconvolute the conformationally averaged J valuesinto conformer populations. While widely applied, this approach assumeshighly idealized models of molecular torsion angles that are likelyto be poor representations of those found in solution. In addition,this treatment often gives negative populations and neglects the presenceof librational averaging of molecular torsion angles. Recentwork in this research group has focused on the developmentof a hybrid experimental-computational method, MA'AT analysis, that provides probability distributions of molecular torsionangles in solution that can be superimposed on those obtained by MD.Ensembles of redundant NMR spin couplings, including (3) J (vicinal), (2) J (geminal), andsometimes (1) J (direct) values, are usedin conjunction with circular statistics to provide single- and multistatemodels of these angles. MA'AT analysis providesaccurate mean torsion angles and circular standard deviations (CSDs)of each mean angle that describe the librational motion about theangle. Both conformational equilibria and dynamics are revealed bythe method. In this Account, the salient features of MA'AT analysis are discussed, including some applications to conformationalproblems involving saccharides and peptides.