Exceptionally small attenuation factors in molecular wires

MA'AT analysis (J. Chem. Inf. Model. 2022, 62, 3135-3141) has been applied to model exocyclic hydroxymethyl group conformation in methyl beta-D-glucopyranoside (beta GlcOMe), methyl beta-D-galactopyranoside (beta GalOMe), and methyl beta-D-mannopyranoside (beta ManOMe) in an unbiased manner. Using up to eight NMR J-couplings sensitive to rotation about the C5-C6 bond (torsion angle omega), two-state models of omega were obtained that are qualitatively consistent with the relative populations of the gg, gt, and tg rotamers reported previously. MA'AT analysis gave consistent unbiased gt tg models of omega in beta GalOMe, with gt more populated than tg and mean values of omega for each population similar to those obtained from aqueous 1-mu s MD simulation. Using different combinations of J-couplings had little effect on the beta GalOMe model in terms of the mean values of omega and circular standard deviations (CSDs). In contrast, MA'AT analysis of omega in beta GlcOMe and beta ManOMe produced more than one two-state model independent of the ensemble of J-values used in the analyses. These models were characterized by gg gt conformer exchange as expected, but the mean values of omega in both conformers varied significantly in the different fits, especially for the gg rotamer. Constrained (biased) MA'AT analyses in which only staggered geometries about omega were allowed gave RMSDs slightly larger than those obtained from the unbiased fits, precluding an assignment of an unbiased model. It is unclear why MA'AT analysis gives consistent and predictable unbiased models of omega in beta GalOMe but not in beta GlcOMe and beta ManOMe. One possibility is that the distribution of omega in one or both of the gg and gt conformers in the latter does not conform to a von Mises function (i.e., is not Gaussian-like), but rather to a broad and/or flat distribution that cannot be fit by the current version of MA'AT. Nevertheless, the results of this study provide new evidence of the ability of MA'AT analysis to treat multi-state conformational exchange using only experimental NMR data, extending recent MA'AT applications to furanosyl ring pseudorotation (Biochemistry 2022, 61, 239-251).