We used force-field-based molecular dynamics to study the interaction between polymers and carbon nanotubes (CNTs). The intermolecular interaction energy between single-walled carbon nanotubes and polymers was computed, and the morphology of polymers adsorbed to the surface of nanotubes was investigated. Furthermore, the "wrapping" of nanotubes by polymer chains was examined. It was found that the specific monomer structure plays a very important role in determining the strength of interaction between nanotubes and polymers. The results of our study suggest that polymers with a backbone containing aromatic rings are promising candidates for the noncovalent binding of carbon nanotubes into composite structures. Such polymers can be used as building blocks in amphiphilic copolymers to promote increased interfacial binding between the CNT and a polymeric matrix.

The interaction of OH-containing compounds with calcite, CaCO(3), such as is required for the processes that control biomineralization, has been investigated in a low-water solution. We used ethanol (EtOH) as a simple, model, OH-containing organic compound, and observed the strength of its adsorption on calcite relative to OH from water and the consequences of the differences in interaction on crystal growth and dissolution. A combination of atomic force microscopy (AFM) and molecular dynamics (MD) simulations showed that EtOH attachment on calcite is stronger than HOH binding and that the first adsorbed layer of ethanol is highly ordered. The strong ordering of the ethanol molecules has important implications for mineral growth and dissolution because it produces a hydrophobic layer. Ethanol ordering is disturbed along steps and at defect sites, providing a bridge from the bulk solution to the surface. The strong influence of calcite in structuring ethanol extends further into the liquid than expected from electrical double-layer theory. This suggests that in fluids where water activity is low, such as in biological systems optimized for biomineralization, organic molecules can control ion transport to and from the mineral surface, confining it to specific locations, thus providing the organism with control for biomineral morphology.

Automated methods for force field parametrization have attracted renewed interest of the community, but the robustness issues associated with the often ill-conditioned nature of parameter optimization have been vastly underappreciated in the recent literature. For this reason, the present paper offers a detailed description of the origin and nature of these issues. This includes a discussion of the RESP charge-fitting model, which does contain explicit robustness-enhancing measures albeit not in the context of bonded parameters, and which forms an inspiration for the present work. It is also discussed how all the bonded parameters in a Class I force field can be simultanteously fit using the Linear Least Squares (LLS) procedure, and a novel restraining strategy is presented that overcomes robustness issues in the LLS fitting of bonded parameters while minimally impacting the fitted values of well-behaved parameters. Two variants of this methodology are then validated through a number of case studies, including the fitting of bond-charge increments, which illustrates the method’s potential for robustly solving general LLS problems beyond force field parametrization.

Polysaccharides control the growth of calcite in coccoliths by adsorbing preferentially onto particular surfaces of the calcite crystal. We chose four units from the coccolith associated polysaccharide (CAP) that is known to promote formation of vicinal faces in Emiliania huxleyi, namely, galactose, mannose, xylose, and rhamnose, and used molecular dynamics simulations to calculate the absorption of oligosaccharide units onto a number of calcite surfaces. The simulations show a wide range of adsorption energies, which depend on the combination of organic molecule and surface. Oligosaccharides on polar surfaces with surplus negative charge have the strongest adsorption, while those on polar surfaces with surplus positive charge have the weakest. Acute stepped vicinal surfaces have stronger adsorption than planar surfaces, while obtuse stepped surfaces have weaker adsorption than the planar surfaces. On the basis of these simulations, the behavior of two saccharides on the calcite {1 0 1 j 4} surface was observed experimentally with atomic force microscopy (AFM) and shown to be consistent with the simulations. This helps explain why the polysaccharides involved in biomineralization have the chemical composition that they do and also suggests criteria for new molecules to control calcite crystal growth.

Replica exchange (REX) is a powerful computational tool for overcoming the quasi-ergodic sampling problem of complex molecular systems. Recently, several multidimensional extensions of this method have been developed to realize exchanges in both temperature and biasing potential space or the use of multiple biasing potentials to improve sampling efficiency. However, increased computational cost due to the multidimensionality of exchanges becomes challenging for use on complex systems under explicit solvent conditions. In this study, we develop a one-dimensional (1D) REX algorithm to concurrently combine the advantages of overall enhanced sampling from Hamiltonian solute scaling and the specific enhancement of collective variables using Hamiltonian biasing potentials. In the present Hamiltonian replica exchange method, termed HREST-BP, Hamiltonian solute scaling is applied to the solute subsystem, and its interactions with the environment to enhance overall conformational transitions and biasing potentials are added along selected collective variables associated with specific conformational transitions, thereby balancing the sampling of different hierarchical degrees of freedom. The two enhanced sampling approaches are implemented concurrently allowing for the use of a small number of replicas (e.g., 6 to 8) in 1D, thus greatly reducing the computational cost in complex system simulations. The present method is applied to conformational sampling of two nitrogen-linked glycans (N-glycans) found on the HIV gp120 envelope protein. Considering the general importance of the conformational sampling problem, HREST-BP represents an efficient procedure for the study of complex saccharides, and, more generally, the method is anticipated to be of general utility for the conformational sampling in a wide range of macromolecular systems.

Invasive infections associated with non-typhoidal Salmonella (NTS) serovars Enteritidis (SE), Typhimurium (STm) and monophasic variant 1,4,[5],12:i:- are a major health problem in infants and young children in sub-Saharan Africa, and currently, there are no approved human NTS vaccines. NTS O-polysaccharides and flagellin proteins are protective antigens in animal models of invasive NTS infection. Conjugates of SE core and O-polysaccharide (COPS) chemically linked to SE flagellin have enhanced the anti-COPS immune response and protected mice against fatal challenge with a Malian SE blood isolate. We report herein the development of a STm glycoconjugate vaccine comprised of STm COPS conjugated to the homologous serovar phase 1 flagellin protein (FliC) with assessment of the role of COPS O-acetyls for functional immunity. Sun-type COPS conjugates linked through the polysaccharide reducing end to FliC were more immunogenic and protective in mice challenged with a Malian STm blood isolate than multipoint lattice conjugates (>95% vaccine efficacy [VE] versus 30–43% VE). Immunization with de-O-acetylated STm-COPS conjugated to CRM197 provided significant but reduced protection against STm challenge compared to mice immunized with native STm-COPS:CRM197 (63–74% VE versus 100% VE). Although OPS O-acetyls were highly immunogenic, post-vaccination sera that contained various O-acetyl epitope-specific antibody profiles displayed similar in vitro bactericidal activity when equivalent titers of anti-COPS IgG were assayed. In-silico molecular modeling further indicated that STm OPS forms a single dominant conformation, irrespective of O-acetylation, in which O-acetyls extend outward and are highly solvent exposed. These preclinical results establish important quality attributes for an STm vaccine that could be co-formulated with an SE-COPS:FliC glycoconjugate as a bivalent NTS vaccine for use in sub-Saharan Africa.

Oligosaccharides and polysaccharides exert numerous functional roles in biology through their structural diversity and conformational properties. To investigate their conformational properties using computational methods, Hamiltonian replica exchange (H-REX) combined with twodimensional grid-based correction maps as biasing potentials (bpCMAP) significantly improves the sampling efficiency about glycosidic linkages. In the current study, we extend the application of H-REX with bpCMAP to complex saccharides and establish systematic procedures for bpCMAP construction, determination of replica distribution, and data analysis. Our main findings are that (1) the bpCMAP for each type of glycosidic linkage can be constructed from the corresponding disaccharide using gas-phase umbrella sampling simulations, (2) the replica distribution can be conveniently determined following the exact definition of the average acceptance ratio based on the assigned distribution of biasing potentials, and (3) the extracted free energy surface (or potential of mean force (PMF)) can be improved using the weighted histogram analysis method (WHAM) allowing for the inclusion of data from the excited state replicas in the calculated probability distribution. The method is applied to a branched N-glycan found on the HIV gp120 protein, and a linear N-glycan. Considering the general importance of N-glycans and the wide appreciation of the sampling problem, the present method represents an efficient procedure for the conformational sampling of complex oligo-and polysaccharides under explicit solvent conditions. More generally, the use of WHAM is anticipated to be of general utility for the calculation of PMFs from H-REX simulations in a wide range of macromolecular systems.

To produce biominerals, such as shells, bones, and teeth, living beings create organic compounds that control the growth of the solid phase. Investigating the atomic scale behavior of individual functional groups at the mineral-fluid interface provides fundamental information that is useful for constructing accurate predictive models for natural systems. Previous investigations of the activity of coccolith-associated polysaccharides (CAP) on calcite, using atomic force microscopy (AFM) [Henriksen, K., Young, J. R., Bown, P. R., and Stipp, S. L. S. Palentology 2004, 43 (Part 3), 725-743] and molecular dynamics (MD) modeling [Yang, M., Stipp, S. L. S., and Harding, J. H. Cryst. Growth Des. 2008, 8 (11), 4066-4074], have suggested that OH functional groups control polysaccharide attachment. The purpose of this work was to characterize, using X-ray reflectivity (XR) combined with molecular dynamics (MD) simulations, the structuring on calcite of a layer of the simplest carbon chain molecule that contains an OH group, ethanol (CH(3)-CH(2)-OH). We found evidence that EtOH forms a highly ordered structure at the calcite surface, where the first layer molecules bond with calcite. The ethanol molecules stand up perpendicularly at the interface or nearly so. As a consequence, the fatty, CH(3) ends form a new surface, about 6 Å from the termination of the bulk calcite, and beyond that, there is a thin gap where ethanol density is low. Following is a more disordered layer that is two to three ethanol molecules thick, about 14 Å, where density more resembles that of bulk liquid ethanol. The good agreement between theory and experiment gives confidence that a theoretical approach can offer information about behavior in more complex systems.