Molecular Modeling of Two Disaccharides Containing Fructopyranose Linked to Glucopyranose

Abstract

Ramachandran energy surfaces for the disaccharides leucrose and turanose were computed using MM3. For each molecule, thirty-two combinations of hydroxyl and primary alcohol group orientations were considered. The calculations used a dielectric constant of 4.0 and the maps were generated on a 20° grid-spacing. The models compared well with the corresponding crystal structures except for significant deviations in some of the anomeric C-O bond lengths.     

Development of a molecular mechanics (MM2) force field for α-chlorosilanes

Molecular mechanics (MM2) parameters for silanes which have a Si-C-Cl fragment have been developed based on available experimental data and ab initio molecular orbital (MO) calculations. Molecular properties, mainly rotational barriers and geometries, of α-chlorosilanes have been studied using our new MM2 parameter set. Changes in the Si-C bond lengths and several bond angles of α-chlorosilanes due to the additional attachment of polar atom(s) have been investigated utilizing ab initio calculations. An electronegativity correction to both bond lengths and angles helps MM2 to reproduce results from ab initio calculations. The new force field has been applied to the conformational analysis of l-(chloromethyl)-1,2-dimethylsilacyclopentane, a model used in our studies of rearrangements of α-halosilanes.     

Effect of inclusion of electron correlation in MM3 studies of cyclic conjugated compounds

Electron correlation at the Møller–Plesset second-order level was incorporated into the π-system portion of MM3 calculations for several conformers of [10]annulene, [18]annulene, bicyclo[5.3.1]undecapentaene, and bicyclo[4.4.1]undecapentaene. The conformers with “localized” C(SINGLE BOND)C π bonds (strongly alternating bond lengths) were found to be of lower energy than their counterparts with “delocalized” C(SINGLE BOND)C π bonds (similar bond lengths) before correlation energy was included. Correlation always lowered the energies of the delocalized conformation more than it did that of the localized conformation, such that often the latter was found to be more stable after correlation energy was included in the calculation. When a delocalized structure was not at a stationary point on the MM3 energy surface, such comparison could not be made. An example is the porphin molecule. © 1998 John Wiley & Sons, Inc. J Comput Chem 19: 475–487, 1998     

Modified MM2 scheme for computation of O?C?N-containing systems

A modification of Allinger's MM2 force field for the anomeric effect in O? C? N systems is presented. For optimal consistency, it was parameterized by alternate use of ab initio (3-21G level) and X-ray results to account for the energetic and structural manifestations of the effect in the gas or condensed phase, respectively. The results obtained with the modified force field are in good agreement with those from both theoretical and experimental methods. The parameterization scheme explicitly treats all structural parameters of the C? O? C? N? C moiety as well as C? N bond lengths in tertiary amines contained within an anomeric unit. In addition, it includes directional H-bond type interactions. A limited number of parameters is put forward, in accord with the general MM2 force-field approach. © 1993 John Wiley & Sons, Inc.     

Molecular mechanics (MM3) parameterization for oxocarbenium ions

The physical properties of a diverse group of 12 oxocarbenium ions have been studied with ab initio calculations at the MP2/6‐31+G* level of theory. Based on theoretically derived properties such as molecular equilibrium geometry, dipole moment, and vibrational frequencies, a molecular mechanics (MM3) force field has been developed with the assistance of the programs TORSMART and MPMSR, components of our artificial parameter development and refinement method. The MM3 force field is now able to reproduce bond lengths, bond angles, moments of inertia, dipole moments, torsional energy profiles, and vibrational frequencies of oxocarbenium ions, which will allow further studies of glycoside hydrolysis and their rates of reaction. © 2000 John Wiley & Sons, Inc. J Comput Chem 21: 329–339, 2000     

A molecular mechanics (MM3) study of fluorinated hydrocarbons

A molecular mechanics study of small saturated hydrocarbons (up to C-6), substituted by up to six fluorines was carried out with the MM3 force field. Perfluorobutane and Teflon were also studied. A parameter set was developed for use in the calculation of bond lengths, bond angles, torsion angles, conformational energies, barriers to rotation, dipole moments, moments of inertia and vibrational frequencies for these compounds. The results are in good agreement with experiment when only one or two fluorines are present, but some rather large discrepancies were noted when the F/H ratio becomes high. These can be taken into account only by using a force field more complicated than MM3. Some of the requirements of such a force field are delineated. Some pertinent ab initio results are also reported in this article.     

Molecular mechanics (MM3) parameterization of hydroxylamine and methyl derivatives

Based on results of electron diffraction, gas phase infrared spectroscopy (IR), and MP2/6-31 + G* ab initio calculations, a set of molecular mechanics (MM3) parameters was developed for molecules containing the N(sp³)—O(sp³) moiety. Using this set of parameters, MM3 is able to reproduce structures (bond lengths and bond angles) and vibrational spectra satisfactorily. © 1994 by John Wiley & Sons, Inc.     

Application of parallel processing techniques to improving the efficiency of MM2 molecular mechanics calculations

The application of parallel processing techniques to molecular mechanics calculations is evaluated. Using the standard molecular mechanics package, MM2, four different parallel versions of the program are implemented in a four-processor computing environment. A set of 529 test structures is used to compare the efficiency of the parallel versions of MM2 to a standard serial version of the program. Statistics describing execution times and program execution cycles are gathered and analyzed. The effects of parallel processing overhead and computer system load are explored, and the practical utility of parallel processing in molecular mechanics is estimated. The results of these parallelization experiments indicate that for geometry optimizations requiring significant amounts of computing time an improvement in program execution speed approaching 50% is realizable. © 1993 John Wiley & Sons, Inc.     

Searching for conformers of nine- to twelve-ring hydrocarbons on the MM2 and MM3 energy surfaces: Stochastic search for interconversion pathways

The stochastic search method was employed to find as many conformers on the MM2 and MM3 energy surfaces as possible for cyclic saturated hydrocarbons with ring sizes from 9 through 12. The number found was 8 MM2 (8 MM3) for 9 rings, 18 MM2 (16 MM3) for 10 rings, 40 MM2 (29 MM3) for 11 rings, and 111 MM2 (90 MM3) for 12 rings. A measure of similarity between pairs of conformers of a compound, called conformational distance, is described. It was used to correlate similar MM2 and MM3 conformers. It was discovered that some conformers on each energy surface are not close to minima on the other surface in rings larger than 9. On refinement with the other optimizer, they changed considerably—going downhill to other previously found minima on the other energy surface or (in a few cases) going to minima which had not been found by direct searches. Conformational distance was also employed as an indication of which pairs of MM2 (or MM3) conformers are likely to interconvert rapidly. A new stochastic procedure of using small kicks was used to search for the most likely interconversion processes among the conformers. There is fairly good agreement between the most facile pathways located by it and unusually short conformational distances. Several additional 12-ring conformers (not found with previous methods) were located through application of this small kick procedure.     

Study of peptide conformation in terms of the ABEEM/MM method

The ABEEM/MM model (atom-bond electronegativity equalization method fused into molecular mechanics) is applied to study of the polypeptide conformations. The Lennard-Jones and torsional parameters were optimized to be consistent with the ABEEM/MM fluctuating charge electrostatic potential. The hydrogen bond was specially treated with an electrostatic fitting function. Molecular dipole moments, dimerization energies, and hydrogen bond lengths of complexes are reasonably achieved by our model, compared to ab initio results. The ABEEM/MM fluctuating charge model reproduces both the peptide conformational energies and structures with satisfactory accuracy with low computer cost. The transferability is tested by applying the parameters of our model to the tetrapeptide of alanine and another four dipeptides. The overall RMS deviations in conformational energies and key dihedral angles for four di- or tetrapeptide, is 0.39 kcal/mol and 7.7 degrees . The current results agree well with those by the accurate ab initio method, and are comparable to those from the best existing force fields. The results make us believe that our fluctuating charge model can obtain more promising results in protein and macromolecular modeling with good accuracy but less computer cost.     

The MM3 force field for amides,polypeptides and proteins

The potential functions for simple amides, several peptides and a small protein have been worked out for the MM3 force field. Structures and energies were fit as previously with MM2, but additionally, we fit the vibrational spectra of the simple amides (average rms error over four compounds, 34 cm^?1), and examined more carefully electrostatic interactions, including charge-charge and charge-dipole interactions. The parameters were obtained and tested by examining four simple amides, five electrostatic model complexes, two dipeptides, six crystalline cyclic peptides, and the protein Crambin. The average root-mean-square deviation from the X-ray structures for the six cyclic peptide crystals was only 0.10 Å for the nonhydrogen atomic positions, and 0.011 Å, 1.0°, and 4.9° for bond lengths, bond angles, and torsional angles, respectively. The parameter set was then further tested by minimizing the high resolution crystal structure of the hydrophobic protein Crambin. The resultant root-mean-square deviations for the non-hydrogen atomic data, in the presence of the crystal lattice, are 0.22 Å, 0.023 Å, 2.0°, and 6.4° for coordinates, bond lengths, bond angles, and torsional angles, respectively.     

Ab initio and density functional theory study of structures and energies for dimethoxymethane as a model for the anomeric effect

Ab initio molecular orbital theory and density functional theory calculations have been carried out on dimethoxymethane as a model for the anomeric effect. We optimized various conformations of dimethoxymethane using Gaussian 92 at the MP2/6-311 + + G**, MP2/DZP + Diffuse, MP2/6-31G**, and Becke3LYP/6-31G** levels of theory. These methods were evaluated based on their performance in reproducing structures and energies of dimethoxymethane when compared to experiment. This study also examined the structure and energy of dimethoxymethane as a function of dihedral angles for examining the anomeric effect at the MP2/6-31G** and Becke3LYP/6-31G** levels of theory. These calculations are qualitatively consistent with the anomeric effect observations in carbohydrates and with earlier calculations. Quantitative comparisons with earlier results reveal that dimethoxymethane has lower total energies, smaller rotational barriers, and shorter bond lengths than was previously determined. The Becke3LYP calculations were also compared to the MP2 results. The density functional theory findings show that the minimum energy structures correspond well with experimental and MP2 data. The total and relative energies from molecular orbital theory and density functional theory vary to some extent. Contour plots of the relative energies of dimethoxymethane were evaluated and compared to a relative energy contour plot determined by MM3. The contour plots were similar, showing slightly larger changes in energies for the MP2 results than for the Becke3LYP results, which in turn were slightly larger than the MM3 results. Density functional theory calculations are an excellent alternative method of calculation due to increased speed and reliable accuracy of the density functional calculations. These results will serve as a benchmark for modelling the anomeric effect in carbohydrates. © 1996 John Wiley & Sons, Inc.     

环多肽晶体的浮动电荷极化力场模拟

利用原子键电负性均衡结合分子力场方法(ABEEM/MM)对五种环多肽晶体进行了研究. 与传统力场相比, 该方法中的静电势包含了分子内和分子间的静电极化作用, 以及分子内电荷转移影响, 同时加入了化学键等非原子中心电荷位点, 合理地体现了分子中的电荷分布. 相对其他极化力场模型, 具有计算量较小的特点. 该模型下计算得到的环多肽分子单元相对实验测得的结构的原子位置、氢键长度和二面角的均方根偏差分别为0.009 nm、0.013 nm和5.16°, 能够很好地重复实验结果. 总体上, 其结果优于或相当于其他力场模型, 适用于对实际蛋白质体系的模拟和研究.     

Correlation effects on the structure and dynamics of the H3O+ hydrate: B3LYP/MM and MP2/MM MD simulations

Two combined quantum mechanics/molecular mechanics (QM/MM) molecular dynamics (MD) simulations, namely B3LYP/MM and MP2/MM, have been performed to investigate the possible influence of electron correlation on the structure and dynamics of the H(3)O(+) hydrate. In comparison to the previously published HF/MM results, both B3LYP/MM and MP2/MM simulations clearly reveal stronger H(3)O(+)-water hydrogen bond interactions, which are reflected in a slightly greater compactness of the H(3)O(+) hydrate. However, the B3LYP/MM simulation, although providing structural details very close to the MP2/MM data, shows an artificially slow dynamic nature of some first shell water molecules as a consequence of the formation of a long-lived H(3)O(+)···H(2)O hydrogen bonding structure.     

Relative stabilities and conformational ring inversion potentials in heterocyclic decalin systems and stereoelectronic implications

The energy differences between stereoisomers and the ring inversion potential surfaces of decalin (1) and various oxadecalins (2, 3), dioxadecalins (4–7), trioxadecalins (8, 9) and tetraoxadecalins (10, 11) were interrogated following the generally accepted scheme of a stepwise conformational six-ring inversion process and using molecular mechanics techniques (MM3 and MM3-GE, i.e. MM3 reparametrized for treatment of the “gauche effect”). The results were compared with some available experimental data and were also used to probe the validity of a recently elaborated protocol for ring-fragment analysis of oxygen-containing bicyclic systems in terms of their interannular fragment components: C---C---C---C, C---C---C---O, C---C---O---C, C---O---C---O---C and O---C---C---O, the latter two with their corresponding stereoelectronic effects, namely, the “anomeric effect” and the “gauche effect”, respectively.     

Producing DFT/MM enzyme reaction trajectories from SCC‐DFTB/MM driving forces to probe the underlying electronics of a glycosyltransferase reaction

The SCC‐DFTB/MIO/CHARMM free energy surface for a glycosyltransferase, TcTS, is benchmarked against a DFT/MM reaction trajectory using the same CHARMM MM force field ported to the NWChem package. The popular B3LYP functional, against which the MIO parameter set was parameterized is used to optimize TS structures and run DFT reaction dynamics. A novel approach was used to generate reaction forces from a SCC‐DFTB/MIO/CHARMM reaction surface to drive B3LYP/6‐31G/MM and B3LYP/6‐31G(d)/MM reaction trajectories. Although TS structures compare favorably, differences stemming primarily from a minimal basis set approximation prevented a successful 6‐31G(d) FEARCF reaction dynamics trajectory. None the less, the dynamic evolution of the B3LYP/6‐31G/MM‐computed electron density provided an opportunity to perform NBO analysis along the reaction trajectory. Here, we illustrate that a successful ab initio reaction trajectory is computationally accessible when the underlying potential energy function of the semi‐empirical method used to produce driving forces is sufficiently close to the ab initio potential. © 2017 Wiley Periodicals, Inc.     

Conformational analysis of thioglycoside derivatives of histo-blood group ABH antigens using an ab initio-derived reparameterization of MM4: implications for design of non-hydrolysable mimetics

Histo-blood group ABH antigens serve as recognition sites for infectious microorganisms and tissue lectins in intercellular communication, e.g. in tumor progression. Thus, they are of interest as a starting point for drug design. In this respect, potent non-hydrolysable derivatives such as thioglycosides are of special interest. As prerequisite to enable estimations of ligand properties relative to their natural counterparts, conformational properties of the thioglycosidic derivatives of ABH trisaccharides and their disaccharide units were calculated using systematic and filtered systematic searches with the MM4 force field. Parameters for the glycosidic torsions of thioglycosides were independently derived from ab initio calculations. The resulting energy deviations required a reparameterization of MM4 to a new parameter set called MM4R. The data sets obtained using MM4R reveal that the thioglycosides have somewhat increased levels of flexibility about the major low-energy conformations shared with the corresponding O-glycosides. In the trisaccharides, the thiosubstitution of the Gal[NAc]α1-3Gal linkage leads to a preference for a conformation which is the secondary minimum of the natural counterparts. This conformation also generates contacts between the N-acetyl group and the fucose moiety in the blood group A derivative. Calculations further indicate that thiosubstitution of only the Fucα1-2Gal linkage does not affect the conformational preferences compared to the natural trisaccharide. Thiosubstitution of both linkages in the trisaccharide results in increased flexibility but the favored conformation of the natural trisaccharides is preferred. The study suggests that thioglycoside derivatives of ABH antigens could have pharmaceutical interest as ligands of lectins and other carbohydrate-binding proteins.     

1D 13C-NMR data as molecular descriptors in spectra--structure relationship analysis of oligosaccharides

Spectra-structure relationships were investigated for estimating the anomeric configuration, residues and type of linkages of linear and branched trisaccharides using 13C-NMR chemical shifts. For this study, 119 pyranosyl trisaccharides were used that are trimers of the α or β anomers of D-glucose, D-galactose, D-mannose, L-fucose or L-rhamnose residues bonded through a or b glycosidic linkages of types 1→2, 1→3, 1→4, or 1→6, as well as methoxylated and/or N-acetylated amino trisaccharides. Machine learning experiments were performed for: (1) classification of the anomeric configuration of the first unit, second unit and reducing end; (2) classification of the type of first and second linkages; (3) classification of the three residues: reducing end, middle and first residue; and (4) classification of the chain type. Our previously model for predicting the structure of disaccharides was incorporated in this new model with an improvement of the predictive power. The best results were achieved using Random Forests with 204 di- and trisaccharides for the training set-it could correctly classify 83%, 90%, 88%, 85%, 85%, 75%, 79%, 68% and 94% of the test set (69 compounds) for the nine tasks, respectively, on the basis of unassigned chemical shifts.     

Anomeric effect in "high energy" phosphate bonds. Selective destabilization of the scissile bond and modulation of the exothermicity of hydrolysis

A natural bonding orbital (NBO) analysis of phosphate bonding and connection to experimental phosphotransfer potential is presented. Density functional calculations with the 6-311++G(d,p) basis set carried out on 10 model phosphoryl compounds verify that the wide variability of experimental standard free energies of hydrolysis (a phosphotransfer potential benchmark) is correlated with the instability of the scissile O-P bond through computed bond lengths. NBO analysis is used to analyze all delocalization interactions contributing to O-P bond weakening. Phosphoryl bond lengths are found to correlate strongest (R = 0.90) with the magnitude of the ground-state n(O) --> sigma*(O-P) anomeric effect. Electron-withdrawing interactions of the substituent upon the sigma(O-P) bonding orbital also correlate strongly with O-P bond lengths (R = 0.88). However, an analysis of sigma*(O-P) and sigma(O-P) populations show that the increase in sigma*(O-P) density is up to 6.5 times greater than the decrease in sigma(O-P) density. Consequently, the anomeric effect is more important than other delocalization interactions in impacting O-P bond lengths. Factors reducing anomeric power by diminishing either lone pair donor ability (solvent) or antibonding acceptor ability (substituent) are shown to result in shorter O-P bond lengths. The trends shown in this work suggest that the generalized anomeric effect provides a simple explanation for relating the sensitivity of the O-P bond to diverse environmental and substituent factors. The anomeric n(O) --> sigma*(O-P) interaction is also shown to correlate strongly with experimentally determined standard free energies of hydrolysis (R = -0.93). A causal mechanism cannot be inferred from correlation. Equally, a P-value of 1.2 x 10(-4) from an F-test indicates that it is unlikely that the ground-state anomeric effect and standard free energies of hydrolysis are coincidentally related. It is found that as the exothermicity of hydrolysis increases, the energy stabilization of the ground-state anomeric effect increases with selective destabilization of the high-energy O-P bond to be broken in hydrolysis. The anomeric effect therefore partially counteracts a larger resonance stabilization of products that makes hydrolysis exothermic and needs to be considered in achieving improved agreement between calculated and empirical energies of hydrolysis. The avenues relating the thermodynamic behavior of phosphates to underlying structural factors via the anomeric effect are discussed.     

New QM/MM implementation of the DFTB3 method in the gromacs package

The approximate density‐functional tight‐binding theory method DFTB3 has been implemented in the quantum mechanics/molecular mechanics (QM/MM) framework of the Gromacs molecular simulation package. We show that the efficient smooth particle–mesh Ewald implementation of Gromacs extends to the calculation of QM/MM electrostatic interactions. Further, we make use of the various free‐energy functionalities provided by Gromacs and the PLUMED plugin. We exploit the versatility and performance of the current framework in three typical applications of QM/MM methods to solve biophysical problems: (i) ultrafast proton transfer in malonaldehyde, (ii) conformation of the alanine dipeptide, and (iii) electron‐induced repair of a DNA lesion. Also discussed is the further development of the framework, regarding mostly the options for parallelization. © 2015 Wiley Periodicals, Inc.