A new derivation of the GLYCAM06 force field, which removes its previous specificity for carbohydrates, and its dependency on the AMBER force field and parameters, is presented. All pertinent force field terms have been explicitly specified and so no default or generic parameters are employed. The new GLYCAM is no longer limited to any particular class of biomolecules, but is extendible to all molecular classes in the spirit of a small-molecule force field. The torsion terms in the present work were all derived from quantum mechanical data from a collection of minimal molecular fragments and related small molecules. For carbohydrates, there is now a single parameter set applicable to both α-and β-anomers and to all monosaccharide ring sizes and conformations. We demonstrate that deriving dihedral parameters by fitting to QM data for internal rotational energy curves for representative small molecules generally leads to correct rotamer populations in molecular dynamics simulations, and that this approach removes the need for phase corrections in the dihedral terms. However, we note that there are cases where this approach is inadequate. Reported here are the basic components of the new force field as well as an illustration of its extension to carbohydrates. In addition to reproducing the gas-phase properties of an array of small test molecules, condensed-phase simulations employing GLYCAM06 are shown to reproduce rotamer populations for key small molecules and representative biopolymer building blocks in explicit water, as well as crystalline lattice properties, such as unit cell dimensions, and vibrational frequencies.

The relationship between the three-dimensional structures of oligosaccharides and polysaccharides and their biological properties has been the focus of many recent studies. The overall conformation of an oligosaccharide depends primarily on the orientation of the torsion angles (, , and ) between glycosyl residues. Numerous experimental studies have shown that in glucopyranosides the -torsion angle (O6-C6-C5-O5) displays a preference for gauche orientations, in disagreement with predictions based on gas-phase quantum mechanics calculations. In contrast, the -angle in galactopyranosides displays a high proportion of the anti-orientation. For oligosaccharides containing glycosidic linkages at the 6-position (136 linked), variations in rotamer population have a direct effect on the oligosaccharides' structure and function, and yet the physical origin of these conformational preferences remains unclear. Although it is generally recognized that the gauche effect in carbohydrates is a solvent-dependent phenomenon, the mechanism through which solvent induces the gauche preference is not understood. In the present work, quantum mechanics and solvated molecular dynamics calculations were performed on two representative carbohydrates, methyl ␣-D-glucopyranoside and methyl ␣-Dgalactopyranoside. We show that correct reproduction of the experimental rotamer distributions about the -angles is obtained only after explicit water is included in the molecular dynamics simulations. The primary role of the water appears to be to disrupt the hydrogen bonding within the carbohydrate, thereby allowing the rotamer populations to be determined by internal electronic and steric repulsions between the oxygen atoms. The results reported here provide a quantitative explanation of the conformational behavior of (136)-linked carbohydrates.T he phenomenon of carbohydrate recognition is critical to many biological functions, including the response of the immune system to bacterial pathogens, the attachment of viral inf luenza particles to host cells, and the hyperacute rejection of tissue transplants from nonhuman sources. Understanding the conformational properties of carbohydrates is essential for the elucidation of their mechanisms of action, which may aid in the design of carbohydrate-based vaccines, antiviral drugs, and other therapeutic agents. A significant amount of research has gone into the study of the three-dimensional structures and dynamics of oligosaccharides and polysaccharides for these reasons (1-18).Unlike polypeptides and proteins, oligosaccharides do not contain secondary-structural motifs and do not form wellorganized tertiary structures in solution. Rather, oligosaccharides often populate multiple conformational families, thus requiring both temporal and spatial descriptors to quantify their conformational properties. Experimental methods such as NMR spectroscopy and x-ray crystallography have a long history of application to carbohydrates. However, these methods generally result in a single three-dimensional model for th...

The role of the binary nucleation of sulfuric acid in aerosol formation and its implications for global warming is one of the fundamental unsettled questions in atmospheric chemistry. We have investigated the thermodynamics of sulfuric acid hydration using ab initio quantum mechanical methods. For H(2)SO(4)(H(2)O)(n) where n = 1-6, we used a scheme combining molecular dynamics configurational sampling with high-level ab initio calculations to locate the global and many low lying local minima for each cluster size. For each isomer, we extrapolated the Møller-Plesset perturbation theory (MP2) energies to their complete basis set (CBS) limit and added finite temperature corrections within the rigid-rotor-harmonic-oscillator (RRHO) model using scaled harmonic vibrational frequencies. We found that ionic pair (HSO(4)(-)·H(3)O(+))(H(2)O)(n-1) clusters are competitive with the neutral (H(2)SO(4))(H(2)O)(n) clusters for n ≥ 3 and are more stable than neutral clusters for n ≥ 4 depending on the temperature. The Boltzmann averaged Gibbs free energies for the formation of H(2)SO(4)(H(2)O)(n) clusters are favorable in colder regions of the troposphere (T = 216.65-273.15 K) for n = 1-6, but the formation of clusters with n ≥ 5 is not favorable at higher (T > 273.15 K) temperatures. Our results suggest the critical cluster of a binary H(2)SO(4)-H(2)O system must contain more than one H(2)SO(4) and are in concert with recent findings (1) that the role of binary nucleation is small at ambient conditions, but significant at colder regions of the troposphere. Overall, the results support the idea that binary nucleation of sulfuric acid and water cannot account for nucleation of sulfuric acid in the lower troposphere.

It has been speculated that the presence of OH(H2O)n clusters in the troposphere could have significant effects on the solar absorption balance and the reactivity of the hydroxyl radical. We have used the G3 and G3B3 model chemistries to model the structures and predict the frequencies of hydroxyl radical/water clusters containing one to five water molecules. The reaction between hydroxyl radical clusters and methane was examined as a function of water cluster size to gain an understanding of how cluster size affects the hydroxyl radical reactivity.

Lipopolysaccharides (LPS) comprise the outermost layer of the Gram-negative bacteria cell envelope. Packed onto a lipid layer, the outer membrane displays remarkable physical-chemical differences compared to cell membranes. The carbohydrate-rich region confers a membrane asymmetry that underlies many biological processes such as endotoxicity, antibiotic resistance, and cell adhesion. Furthermore, unlike membrane proteins from other sources, integral outer-membrane proteins do not consist of transmembrane α helices; instead they consist of antiparallel β-barrels, which highlights the importance of the LPS membrane as a medium. In this work, we present an extension of the GLYCAM06 force field that has been specifically developed for LPS membranes using our Wolf2Pack program. This new set of parameters for lipopolysaccharide molecules expands the GLYCAM06 repertoire of monosaccharides to include phosphorylated N- and O-acetylglucosamine, 3-deoxy-d-manno-oct-2-ulosonic acid, l-glycero-D-manno-heptose and its O-carbamoylated variant, and N-alanine-d-galactosamine. A total of 1 μs of molecular dynamics simulations of the rough LPS membrane of Pseudomonas aeruginosa PA01 is used to showcase the added parameter set. The equilibration of the LPS membrane is shown to be significantly slower compared to phospholipid membranes, on the order of 500 ns. It is further shown that water molecules penetrate the hydrocarbon region up to the terminal methyl groups, much deeper than commonly observed for phospholipid bilayers, and in agreement with neutron diffraction measurements. A comparison of simulated structural, dynamical, and electrostatic properties against corresponding experimentally available data shows that the present parameter set reproduces well the overall structure and the permeability of LPS membranes in the liquid-crystalline phase.

The Gaussian-3 (G3) model chemistry method has been used to calculate the relative deltaG(o) values for all possible conformers of neutral clusters of water, (H2O)n, where n = 3-5. A complete 12-fold conformational search around each hydrogen bond produced 144, 1728, and 20,736 initial starting structures of the water trimer, tetramer, and pentamer. These structures were optimized with PM3, followed by HF/6-31G* optimization, and then with the G3 model chemistry. Only two trimers are present on the G3 potential energy hypersurface. We identified 5 tetramers and 10 pentamers on the potential energy and free-energy hypersurfaces at 298 K. None of these 17 structures were linear; all linear starting models folded into cyclic or three-dimensional structures. The cyclic pentamer is the most stable isomer at 298 K. On the basis of this and previous studies, we expect the cyclic tetramers and pentamers to be the most significant cyclic water clusters in the atmosphere.

With improvements in computer speed and algorithm efficiency, MD simulations are sampling larger amounts of molecular and biomolecular conformations. Being able to qualitatively and quantitatively sift these conformations into meaningful groups is a difficult and important task, especially when considering the structure-activity paradigm. Here we present a study that combines two popular techniques, principal component (PC) analysis and clustering, for revealing major conformational changes that occur in molecular dynamics (MD) simulations. Specifically, we explored how clustering different PC subspaces effects the resulting clusters versus clustering the complete trajectory data. As a case example, we used the trajectory data from an explicitly solvated simulation of a bacteria’s L11·23S ribosomal subdomain, which is a target of thiopeptide antibiotics. Clustering was performed, using K-means and average-linkage algorithms, on data involving the first two to the first five PC subspace dimensions. For the average-linkage algorithm we found that data-point membership, cluster shape, and cluster size depended on the selected PC subspace data. In contrast, K-means provided very consistent results regardless of the selected subspace. Since we present results on a single model system, generalization concerning the clustering of different PC subspaces of other molecular systems is currently premature. However, our hope is that this study illustrates a) the complexities in selecting the appropriate clustering algorithm, b) the complexities in interpreting and validating their results, and c) by combining PC analysis with subsequent clustering valuable dynamic and conformational information can be obtained.Electronic supplementary materialThe online version of this article (doi:10.1007/s00894-012-1563-4) contains supplementary material, which is available to authorized users.

Not only steric protection by bulky substituents but also intramolecular N→Sn coordination makes possible the isolation and characterization of dimeric organotin(I) compounds such as [{2,6‐(Me2NCH2)2C6H3}Sn]2 (see structure), which according to a crystallographic study exhibits a SnSn bond length of 2.9712(12) Å.