Flexibility at a glycosidic linkage revealed by molecular dynamics, stochastic modeling, and ¹³C NMR spin relaxation: conformational preferences of α-l-Rhap-α-(1 → 2)-α-l-Rhap-OMe in water and dimethyl sulfoxide solutions

Abstract

The monosaccharide L-rhamnose is common in bacterial polysaccharides and the disaccharide α-L-Rhap-α-(1 → 2)-α-L-Rhap-OMe represents a structural model for a part of Shigella flexneri O-antigen polysaccharides. Utilization of [1'-(13)C]-site-specific labeling in the anomeric position at the glycosidic linkage between the two sugar residues facilitated the determination of transglycosidic NMR (3)JCH and (3)JCC coupling constants. Based on these spin-spin couplings the major state and the conformational distribution could be determined with respect to the ψ torsion angle, which changed between water and dimethyl sulfoxide (DMSO) as solvents, a finding mirrored by molecular dynamics (MD) simulations with explicit solvent molecules. The (13)C NMR spin relaxation parameters T1, T2, and heteronuclear NOE of the probe were measured for the disaccharide in DMSO-d6 at two magnetic field strengths, with standard deviations ≤1%. The combination of MD simulation and a stochastic description based on the diffusive chain model resulted in excellent agreement between calculated and experimentally observed (13)C relaxation parameters, with an average error of <2%. The coupling between the global reorientation of the molecule and the local motion of the spin probe is deemed essential if reproduction of NMR relaxation parameters should succeed, since decoupling of the two modes of motion results in significantly worse agreement. Calculation of (13)C relaxation parameters based on the correlation functions obtained directly from the MD simulation of the solute molecule in DMSO as solvent showed satisfactory agreement with errors on the order of 10% or less.

Multiscale modeling for interpreting nuclear magnetic resonance relaxation in flexible molecules

“…While in principle standard all‐atom MD simulations may be used to evaluate Equation , computation time is at present still prohibitive, especially for complex flexible systems (e.g., proteins). Interested readers can find a short discussion and comparison between NMR calculations done using all‐atom MD simulations or a coarse‐grained model (the DCM, in particular) in the R2R paper …”

“…Thus, under the DCM paradigm, the problem of the selection of the relevant coordinates is moved to the skimming of the set of the torsion angles of the molecule. While such a pre‐selection of the kind of degrees of freedom can be considered a limitation, the DCM model has been used with success in interpreting the magnetic spectroscopy of very different systems, and in all cases resorting to a fitting procedure was extremely limited if not necessary at all, making the whole approach predictive at least for small molecules.…”

“…The integrated computational approach to NMR relaxation has been applied to the study of a number of open‐chain polisaccharides, with two, three, and five sugar units . In this tutorial review, we discuss our most recent case‐study, that is, the NMR relaxation of the α ‐L‐Rha p ‐ α ‐(1 →2)‐ α ‐L‐Rha p ‐OMe (R2R) disaccharide in dimethyl sulfoxide at 298 K. Figure reports the molecular structure together with the corresponding DCM model adopted for the molecule.…”

“…The next quantity to be parametrized is the generalized diffusion tensor, which can be evaluated by the aforementioned program DITE . The generalized diffusion tensor, once devoid of the translational part, is represented by a 4 × 4 matrix.…”

Differential Dynamics at Glycosidic Linkages of an Oligosaccharide as Revealed by 13C NMR Spin Relaxation and Stochastic Modeling

“…In particular, we employed the diffusive chain model (DCM), 14 which proved very effective to predict NMR relaxation data of 'linear' oligosaccharides, with two, three, and five sugar units. 15,16,17 The method is based on the description of the internal degrees of freedom (dof) of a molecule in terms of bonds, bond angles and dihedral angles. The former two types of internal dof are considered fast and therefore not relevant to NMR-based investigations of molecular structure and dynamics.…”