Conformational analysis seeks to describe the molecular shape of a given molecule. This is especially important with regard to understanding the interactions between small molecules such as carbohydrates and proteins. The inherent structural flexibility of carbohydrates allows them to occupy a broad conformational space. Experimental methods, such as quantitative NOE and coupling constant measurements derived from NMR experiments, can be used to describe the molecular shape of carbohydrates. For this, the use of Karplus equations as an empirical relationship between a given torsion angle and the corresponding coupling constant from an NMR experiment has been well established in the literature. However, the time-averaged nature of the NMR measurements and the fact that a measured coupling constant corresponds to multiple torsion angles in a Karplus equation are not captured by static models. Thus, dynamic computational methods need to be used to aid in the conformational analysis. Multiple Karplus equations have been derived for both homonuclear and heteronuclear coupling in carbohydrates. However, these are not applicable to ester-linked carbohydrate derivatives, such as acetylated carbohydrates or uronate-linked compounds, where the hybridization of the ester carbon (sp2) differs from those in the published Karplus equations (sp3). As such, a Karplus equation was derived using both computational QM and MD methods and experimental NMR data for the C(sp2)OCH torsion angle based on 6-acetyl-α/β-D-glucose. Here we present the application of this particular Karplus equation to several relevant ester-functionalized carbohydrate derivatives and ester-linked disaccharide analogs to establish their solution state structure. Heteronuclear 3J coupling constants were measured using a J-resolved HMBC experiment. Molecular dynamics trajectories run for 500ns were used to establish the conformational space of the respective compounds using the carbohydrate-specific GLYCAM06 force field. This allowed for the calculation of time-averaged 3J coupling constant values from the torsion angle distributions, which were compared with the experimental values to establish the validity of the methodology.

Application of newly developed Karplus equations for C(sp2)-O-C-H dihedral angles to the conformational analysis of ester linked carbohydrate derivatives

253rd National Meeting (2017)

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