Conformational Properties of α- or β-(1→6)-Linked Oligosaccharides: Hamiltonian Replica Exchange MD Simulations and NMR Experiments

Abstract

Conformational sampling for a set of ten α- or β-(1→6)-linked oligosaccharides has been studied using explicit solvent Hamiltonian Replica Exchange (HREX) simulations and NMR spectroscopy techniques. Validation of the force field and simulation methodology is done by comparing calculated transglycosidic J-coupling constants and proton-proton distances with the corresponding NMR data. Initial calculations showed poor agreement, for example, with > 3 Hz deviation of the calculated 3J(H5,H6R) values from the experimental data, prompting optimization of the ω torsion angle parameters associated with (1→6)-linkages. The resulting force field is in overall good agreement (i.e. within ~ 0.5 Hz deviation) from experimental 3J(H5,H6R) values, although some small limitations are evident. Detailed hydrogen bonding analysis indicates that most of the compounds lack direct intramolecular H-bonds between the two monosaccharides; however, minor sampling of the O6· · ·HO2′ hydrogen bond is present in three compounds. The results verify the role of the gauche effect between O5 and O6 atoms in gluco- and manno-configured pyranosides causing the ω torsion angle to sample an equilibrium between the gt and gg rotamers. Conversely, galacto-configured pyranosides sample a population distribution in equilibrium between gt and tg rotamers, while the gg rotamer populations are minor. Water radial distribution functions suggest decreased accessibility to the O6 atom in the (1→6)-linkage as compared to the O6' atom in the non-reducing sugar. The role of bridging water molecules between two sugar moieties on the distributions of ω torsion angles in oligosaccharides is also explored.

CHARMM additive and polarizable force fields for biophysics and computer-aided drug design

“…Subsequently, the model has been applied to study glycopeptides, including the anti-proliferative factor, 73 and validated against NMR data for di- and trisaccharides; 74 these efforts included targeting the 1–6 linkage, which led to additional optimization of associated dihedral parameters. 75 The presence of a broad carbohydrate model that is consistent with the remainder of the CHARMM36 force field is anticipated to facilitate studies of complex systems, such as glycolipids, glycoproteins and a range of carbohydrate-containing antibiotics. 76 …”

Conformational Sampling of Oligosaccharides Using Hamiltonian Replica Exchange with Two-Dimensional Dihedral Biasing Potentials and the Weighted Histogram Analysis Method (WHAM)

“…Traditionally, only the ground-state, unbiased replica is used for data analysis. 15, 17, 50-51, 62-63 In this study, we propose to combine all the replicas with the weighted histogram analysis method (WHAM) to obtain an optimal distribution under the original potential of the system. Following the original WHAM 64 implementation, the probability distribution from H-REX can be expressed as the combination of the distribution from each replica, 64-65 …”

“…9-10 In addition, the variations also impact the 3D conformational properties of these molecules, which has stimulated both experimental and theoretical studies in recent years. 11-17 …”

“…49-50 Our previous studies show that H-REX simulations with 1D and 2D biasing potentials applied to the glycosidic linkage dihedrals can greatly enhance conformational sampling for disaccharides and for disaccharides in a glycopeptide. 15, 17 In addition, H-REX has been adopted using a 2D Gaussian-like biasing potential for each linkage in di- and trisaccharides in solution. 51 In the studies in our laboratory the 2D biasing potentials were constructed as the negative of the potential of mean force (PMF) along two linkage dihedrals using the grid-based correction map (CMAP) method, which was originally developed for the protein backbone Φ/Ψ dihedrals in the CHARMM force field.…”

An Unusual Carbohydrate Conformation is Evident in Moraxella catarrhalis Oligosaccharides

“…In order to support the interpretation of the NMR results one would aim at calculating a representative conformational ensemble using molecular dynamics (MD) simulations at room temperature in explicit solvent and compare ensemble statistics of H-H distances with effective NOE distances calculated from relative NOE signal intensities. Despite significant improvements in the development of carbohydrate force fields and in sampling technology like accelerated molecular dynamics [22], replica-exchange molecular dynamics [23][24][25] and Hamiltonian replica-exchange simulation [26][27][28][29], it is still very difficult to generate efficiently and reliably a converged room-temperature ensemble in explicit solvent that provides a basis for reliable interpretation and also to some extent validation of the NMR data. In the case of a discrepancy between the ensemble averaged reff and the effective NOE distance it will remain unclear whether the measured NOE intensity or the simulation results are in question.…”