Monosaccharide derivatives such as xylose, fucose, N-acetylglucosamine (GlcNAc), N-acetylgalactosamine (GlaNAc), glucuronic acid, iduronic acid, and N-acetylneuraminic acid (Neu5Ac) are important components of eukaryotic glycans. The present work details development of force-field parameters for these monosaccharides and their covalent connections to proteins via O-linkages to serine or threonine sidechains and via N-linkages to asparagine sidechains. The force field development protocol was designed to explicitly yield parameters that are compatible with the existing CHARMM additive force field for proteins, nucleic acids, lipids, carbohydrates, and small molecules. Therefore, when combined with previously developed parameters for pyranose and furanose monosaccharides, for glycosidic linkages between monosaccharides, and for proteins, the present set of parameters enables the molecular simulation of a wide variety of biologically-important molecules such as complex carbohydrates and glycoproteins. Parametrization included fitting to quantum mechanical (QM) geometries and conformational energies of model compounds, as well as to QM pair interaction energies and distances of model compounds with water. Parameters were validated in the context of crystals of relevant monosaccharides, as well NMR and/or x-ray crystallographic data on larger systems including oligomeric hyaluronan, sialyl Lewis X, O- and N-linked glycopeptides, and a lectin:sucrose complex. As the validated parameters are an extension of the CHARMM all-atom additive biomolecular force field, they further broaden the types of heterogeneous systems accessible with a consistently-developed force-field model.
Presented is an extension of the CHARMM additive all-atom carbohydrate force field to enable the modeling of phosphate and sulfate linked to carbohydrates. The parameters are developed in a hierarchical fashion using model compounds containing the key atoms in the full carbohydrates. Target data for parameter optimization included full two-dimensional energy surfaces defined by the glycosidic dihedral angle pairs in the phosphate/sulfate model compound analogs of hexopyranose monosaccharide phosphates and sulfates, as determined by quantum mechanical (QM) MP2/cc-pVTZ single point energies on MP2/6-31+G(d) optimized structures. In order to achieve balanced, transferable dihedral parameters for the dihedral angles, surfaces for all possible anomeric and conformational states were included during the parametrization process. In addition, to model physiologically relevant systems both the mono- and di-anionic charged states were studied for the phosphates. This resulted in over 7000 MP2/cc-pVTZ//MP2/6-31G+(d) model compound conformational energies which, supplemented with QM geometries, were the main target data for the parametrization. Parameters were validated against crystals of relevant monosaccharide derivatives obtained from the Cambridge Structural Database (CSD) and larger systems, namely inositol-(tri/tetra/penta) phosphates non-covalently bound to the pleckstrin homology (PH) domain and oligomeric chondroitin sulfate in solution and in complex with cathepsin K protein.
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.
A detailed investigation of the conformational properties of all the biologically relevant O-glycosidic linkages using the Hamiltonian replica exchange (HREX) simulation methodology and the recently developed CHARMM carbohydrate force field parameters is presented. Fourteen biologically relevant O-linkages between five sugars, N-acetylgalactosamine (GalNAc), N-acetylglucosamine (GlcNAc), D-glucose (Glc), D-mannose (Man) and L-fucose (Fuc) and the amino acids Ser and Thr were studied. The force field was tested by comparing the simulation results of the model glycopeptides to various NMR 3J couplings, NOE distances and data from MD with time-averaged restraints (tar-MD). The results show the force field to be in overall agreement with experimental and previous tar-MD simulations, although some small limitations are identified. An in depth hydrogen bond and bridging water analysis revealed an interplay of hydrogen bonding and bridge water interactions influencing the geometry of the underlying peptide backbone, with the O-linkages favoring extended β-sheet and PPII conformations over the compact αR helical conformation. The newly developed parameters were also able to identify hydrogen bonding and water mediated interactions between O-linked sugars and proteins. These results indicate that the newly developed parameters in tandem with HREX conformational sampling provide the means to study glycoproteins in the absence of targeted NMR restraint data.
With most of the early experiments reporting a wide range of electronic properties for DNA, varying from insulating, semiconducting, and conducting to even induced superconductivity, the conductivity of DNA still remains a challenge. To this end, theoretical studies have greatly aided in explaining the observed conductance behavior of DNA. Theoretical charge-transfer studies of DNA can be divided into two broad categories, model calculations and ab initio calculations. In this Perspective, we discuss a few results from both categories and highlight the importance of both methods. The aim is to provide an overview of the theoretical methods that are used to study DNA conductivity, highlighting their strengths and deficiencies.
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