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Neutron diffraction with isotopic substitution (NDIS) experiments were done on both natural abundance potassium and isotopically labeled 41KCl heavy water solutions to characterize the solvent structuring around the potassium ion in water. Preliminary measurements suggested that the literature value for the coherent neutron scattering length (2.69 fm) for 41K was significantly in error. This value was remeasured using a neutron powder diffractometer and found to be 2.40 fm. This revision increases significantly the contrast between the natural abundance K and 41K by about 30% (from 1.0 to 1.3 fm). The experimentally determined structure factor of the potassium ion was then compared to that calculated from molecular dynamics (MD) simulations. Previous neutron scattering measurements of potassium gave a solvation number of 5.5 (see below). In this study, the NDIS and MD results are in good agreement and allowed us to derive a coordination number of 6.1 for water molecules and 0.8 for chloride ions around each K+ ion in 4 molal aqueous KCl solution.

Insight into the molecular interactions of homotactic and heterotactic association of caffeine and pyridine in aqueous solution is given on the basis of both experimental and simulation studies. Caffeine is about 5 times more soluble in a 3 m aqueous pyridine solution than it is in pure water (an increase from ∼0.1 m to 0.5 m). At this elevated concentration the system becomes suitable for neutron scattering study. Caffeine-pyridine interactions were studied by neutron scattering and molecular dynamics simulations, allowing a detailed characterization of the spatial and orientational structure of the solution. It was found that while pyridine-caffeine interactions are not as strong as caffeine-caffeine interactions, the pyridine-caffeine interactions still significantly disrupted caffeine-caffeine stacking. The alteration of the caffeine-caffeine stacking, occasioned by the presence of pyridine molecules in solution and the consequent formation of heterotactic interactions, leads to the experimentally detected increase in caffeine solubility.

Many important biological solutes possess not only polar and hydrogen bonding functionalities, but also weakly-hydrating, or hydrophobic, surfaces. Theories of the hydration of such surfaces predict that their solvent interactions will change from a wetting type interaction to a dewetting regime as a function of the solute size, with a gradual transition in behavior taking place around characteristic lengths of ~ 1 nm. Aggregations of non-polar species over this size range will undergo a transition from being dominated by entropy to being dominated by enthalpy. These transitions can be understood in part in terms of the geometries required of the solvating water molecules. We report here a series of simulations in aqueous solution of organic molecules with planar faces of increasing size, ranging from cyclopropane to circumcircumcoronene, in order to explore the transition in behavior for such solutes as their size increases. For this series, the dewetting transition occurred gradually, converging asymptotically to a limiting separation value for first layer water molecules of around 3.3 Å, while the transition in hydrogen bonding orientational structure occurred between cyclopropane and cyclopentadene. Water immediately adjacent to the largest planar hydrophobic surfaces oriented in ways that resembled on average the structural organization of the basal planes of ice.

The dynamical and structural properties of caffeine solutions at the solubility limit have been investigated as a function of temperature by means of MD simulations, static and dynamic light scattering, and small angle neutron scattering experiments. A clear picture unambiguously supported by both experiment and simulation emerges: caffeine self-aggregation promotes the formation of two distinct types of clusters: linear aggregates of stacked molecules, formed by 2-14 caffeine molecules depending on the thermodynamic conditions and disordered branched aggregates with a size in the range 1000-3000 Å. While the first type of association is well-known to occur under room temperature conditions for both caffeine and other purine systems, such as nucleotides, the presence of the supramolecular aggregates has not been reported previously. MD simulations indicate that branched structures are formed by caffeine molecules in a T-shaped arrangement. An increase of the solubility limit (higher temperature but also higher concentration) broadens the distribution of cluster sizes, promoting the formation of stacked aggregates composed by a larger number of caffeine molecules. Surprisingly, the effect on the branched aggregates is rather limited. Their internal structure and size do not change considerably in the range of solubility limits investigated.

Many important biological solutes possess not only polar and hydrogen-bonding functionalities but also weakly hydrating, or hydrophobic, surfaces. While the aggregation of these hydrophobic surfaces has been shown to play an important role in the aggregation of individual chains of cellulose, it is not known whether the water structuring imposed by these hydrophobic surfaces more closely resembles that associated with small hydrophobic solutes like methane and fats or more closely resembles that associated with extended hydrophobic surfaces like mica or waxy planes. By using molecular dynamics simulations to characterize the water molecule orientations over different regions of the 100 surface of cellulose in contact with water, it was found that the hydrophobic strips of the cellulose crystal are sufficiently narrow that they hydrate like a fatty acid chain, rather than like a more extended surface, suggesting that their aggregation would be dominated by entropy rather than enthalpy.

The structure of aqueous solutions of methyl β-D-ribofuranoside was investigated by coupling molecular dynamics (MD) simulations and neutron scattering measurements with isotopic substitution. Using a sample of the sugar isotopically-labeled at a single unique position, neutron scattering structure factors and radial distribution functions can be compared with MD simulations constrained to different conformations to determine which conformer best fits the experimental results. Three different simulations were performed with the methyl ether group of the sugar unconstrained and constrained in each of its staggered orientations. The results of the unconstrained simulation showed that the methyl ester group occupied predominantly the 300° position, which is in agreement with the diffraction experimental results. This result suggests that the molecular mechanics force field used in the simulation adequately describes the conformation of the 1-methyl ether group in the methyl β-D-ribofuranoside.

Molecular dynamics simulations were carried out on a system of caffeine interacting with the sugar alcohol sorbitol. The system examined had a caffeine concentration 0.083 m and a sugar concentration 1.08 m. The trajectories of all molecules in the system were collected over a period of 80 ns and analyzed to determine whether there is any tendency for sorbitol to bind to caffeine, and if so, by what mechanism. The results show that the sorbitol molecules have an affinity for the caffeine molecules and that the binding occurred by the interaction of the aliphatic hydrophobic protons of the sugar with the caffeine face. This intermolecular association via face-to-face stacking, as suggested by simulation studies, is similar to that found for sucrose and for D-glucose, which overwhelmingly exists in the pyranose ring chair form in aqueous solution, as well as for caffeine-caffeine association. The sorbitol molecules, however, exist as relatively extended chains and are, therefore, topologically quite different from the sugars sucrose and glucose. The comparison of the average conformation of sorbitol molecules bound to caffeine with that of molecules in the free state shows a substantial similarity.

During the last few decades it has been ascertained that base stacking is one of the major contributions stabilizing nucleic acid conformations. However, the understanding of the nature of the interactions involved in the stacking process remains under debate and it is a subject of theoretical and experimental studies. Structural similarity between purine bases (guanine and adenine) in DNA and the caffeine molecule makes caffeine an excellent model for the purine bases. The present study clearly shows that dipolar interactions play a fundamental role in determining stacking of purine molecules in solution. In order to reach this achievement, polarized ultraviolet Raman resonant scattering experiments have been carried out on caffeine aqueous solutions as a function of concentration and temperature. The investigation pointed out at the aggregation and solvation properties, particularly at elevated temperatures. Kubo-Anderson theory was used as a framework to investigate the non-coincidence effect (NCE) occurring in the totally symmetric breathing modes of the purine rings, and in the bending modes of the methyl groups of caffeine. The NCE concentration dependence shows that caffeine aggregation at 80 °C occurs by planar stacking of the hydrophobic faces. The data clearly indicate that dipolar interactions determine the reorientational motion of the molecules in solution and are the driving force for the stacking of caffeine. In parallel, the observed dephasing times imply a change in caffeine interactions as a function of temperature and concentration. A decrease, at low water content, of the dephasing time for the ring breathing vibration mode indicates that self-association alters the solvation structure that is detectable at low concentration. These results are in agreement with simulation predictions and serve as an important validation of the models used in those calculations.

Molecular dynamics simulations were carried out on several systems of caffeine interacting with simple sugars. These included a single caffeine molecule in a 3 molal solution of α-D-glucopyranose, at a caffeine concentration of 0.083 molal; a single caffeine in a 3 molal solution of β-D-glucopyranose, and a single caffeine molecule in a 1.08 molal solution of sucrose (table sugar). Parallel Nuclear Magnetic Resonance titration experiments were carried out on the same solutions under similar conditions. Consistent with previous thermodynamic experiments, the sugars were found to have an affinity for the caffeine molecules in both the simulations and experiments, and that the binding in these complexes occurs by face-to-face stacking of the hydrophobic triad of protons of the pyranose rings against the caffeine face, rather than by hydrogen bonding. For the disaccharide, the binding occurs via stacking of the glucose ring against the caffeine, with a lesser affinity for the fructose observed. These findings are consistent with the association being driven by hydrophobic hydration, and are similar to the previously observed binding of glucose rings to various other planar molecules, including indole, serotonin, and phenol.

A combined solid-state NMR and Molecular Dynamics simulation study of cellulose in urea aqueous solution and in pure water was conducted. It was found that the local concentration of urea is signif ...

Molecular dynamics simulations were carried out on a system of eight independent caffeine molecules in a periodic box of water at 300 K, representing a solution near the solubility limit for caffeine at room temperature, using a newly-developed CHARMM-type force field for caffeine in water. Simulations were also conducted for single caffeine molecules in water using two different water models (TIP3P and TIP4P). Water was found to structure in a complex fashion around the planar caffeine molecules, which was not sensitive to the water model used. As expected, extensive aggregation of the caffeine molecules was observed, with the molecules stacking their flat faces against one another like coins, with their methylene groups staggered to avoid steric clashes. A dynamic equilibrum was observed between large n-mers, including stacks with all eight solute molecules, and smaller clusters, with the calculated osmotic coefficient being in acceptable agreement with the experimental value. The insensitivity of the results to water model and the congruence with experimental thermodynamic data suggest that the observed stacking interactions are a realistic representation of the actual association mechanism in aqueous caffeine solutions.

Small angle neutron scattering (SANS) and molecular dynamics (MD) simulations were used to characterize the long range structuring (aggregation) of aqueous solutions of isopropanol (IPA) and pyridine, and the effect on structuring of guanidinium chloride (GdmCl). These solutes serve as highly soluble analogs of the non-polar aliphatic (IPA), and aromatic (pyridine) side chains of proteins. SANS data showed that isopropanol and pyridine both form clusters in water resulting from interaction between non-polar groups of the solutes, with pyridine aggregation producing longer-range structuring than isopropanol in 3 molal solutions. Addition of GdmCl at 3 molal concentration considerably reduced pyridine aggregation, but had no effect on isopropanol aggregation. MD simulations of these solutions support the conclusion that long range structuring involves hydrophobic solute interactions, and that Gdm+ interacts with the planar pyridine group to suppress pyridine-pyridine interactions in solution. Hydrophobic interactions involving the aliphatic groups of isopropanol were unaffected by GdmCl, indicating that the planar and weakly hydrated Gdm+ cation cannot make productive interactions with the highly curved or “lumpy” aliphatic groups of this solute. These observations support the conclusion that the effects of Gdm+ ions on protein-stabilizing interactions involving aromatic amino acid side chains make significant contributions to the denaturant activity of GdmCl, whereas interactions with the “lumpy” aliphatic side chains are likely to be less important.

Neutron diffraction with isotopic substitution (NDIS) experiments and molecular dynamics (MD) simulations have been used to study the structuring in aqueous solution of two cesium salts, cesium carbonate, and cesium nitrate. As was previously found for guanidinium salts of carbonate, mesoscopic-scale clusters were seen to form in the Cs2CO3 solution both in the MD simulations and in the diffraction experiments. No such large scale ion clusters were found in the CsNO3 solutions in either the modeling or experiments. The results are dominated by the strength and geometry of the direct first-neighbor interactions, which explain the differences in the clustering behavior between the two solutions without need to refer to longer-range water-water structuring.

Neutron diffraction experiments were carried out at ambient temperature on aqueous solutions of glucose at concentrations of 1, 3, and 5 molal. The difference methods of neutron diffraction and isotopic substitution were used to determine various structure factors associated with all the exchangeable hydrogen atoms of the solutions. The results imply that the hydration of the glucose molecule is not concentration sensitive. It is also found that the average water structure itself is relatively unperturbed by the presence of glucose.

The solution conformation of neocarrabiose 41-sulfate, which is a building block of κ-carrageenan, was investigated by a combination of molecular dynamics simulations and 1H NMR experiments. The calculated Ramachandran-type potential energy map for the glycosidic torsion angles φ and ψ of this dimer showed that there are two principal minimum-energy conformations, designated here as “a” and “b”. Comparison of the depths of these minima and the MD trajectories started from each minimum indicated that in a vacuum the molecular conformation in the “a” well is more stable than that in the “b” well. On the other hand, MD simulations in water showed that trajectories started from each minimum position stayed within their respective wells throughout the time courses of the simulations. However, analysis of the hydration water around the molecule indicated that the stability of the molecular conformation in the “a” well would be favored by solvation compared to the “b” well. Analysis of the experimental NOE−NMR d...

Molecular dynamics simulations employing umbrella sampling techniques have been used to calculate the potential of mean force (pmf) for the binding of a β-d-glucopyranose molecule to a benzene molecule in aqueous solution, as a model for the binding of sugar substrates to phenylalanine residues in proteins. The interaction of these two molecules was found to be strongly affected by hydration, as expected, with their nonpolar faces pairing by hydrophobic association to minimize the exposure of apolar groups to water. The pmf for the approach of these molecules is oscillatory in character, with two primary low-energy minima separated by a high free energy barrier, and with the net binding energy being approximately 1.1 kcal/mol and the intervening barrier being almost 2 kcal/mol. A third, weaker minimum was observed between 11 and 12 A. The oscillatory nature of the pmf results from the successive removal of water layers between the two molecules as they approach one another.

Molecular dynamics simulations employing adaptive umbrella sampling have been used to calculate the Ramachandran conformational potential of mean force in aqueous (TIP3P) solution for the α(1→4)-linked dimer of d-xylopyranose (4-O-α-d-xylopyranosyl-α-d-xylopyranose), a pentose analogue of maltose and a useful general model for the effects of solvent structuring upon biopolymer hydration. The vacuum adiabatic energy map for this molecule closely resembles that for maltose, but the solution pmf is quite different, with one of the principal vacuum minima almost completely disappearing in solution and with the global minimum-energy conformation being a new minimum which does not occur at all on the vacuum surface. This conformation is apparently stabilized by a water molecule which hydrogen bonds to a hydroxyl group on each ring, bridging between the two rings. The new conformation also places the two hydrophobic methylene groups almost in van der Waals contact, reducing their exposed surface area. Unfortunat...

Recently, it was shown using structural neutron diffraction with isotopic substitutions (NDIS) measurements, combined with molecular dynamics simulations, that in an aqueous solution of D-xylose the hydroxyl group on the C4 position does not significantly occupy the position trans to the H4 atom. Here, a similar combination of NDIS and MD studies is described which uses D-xylose deuterated at the C5 position to further characterize this hydroxyl conformation as being trans to the C5 atom, as predicted by constrained MD simulations, confirming the previous study.

Molecular dynamics simulations have been used to model the flexibility of the seven-sugar oligosaccharide of the lectin from Erythrina corallodendron in three separate simulations: one of the isolated oligosaccharide in vacuo, one of the oligosaccharide in solution and one of the oligosaccharide linked to the protein in solution. Adiabatic conformational energy maps were prepared for each of the disaccharide linkages as a means of interpreting the observed dynamics and conformational averages in terms of intramolecular energy. The inclusion of aqueous solvent molecules appears to be necessary to reproduce the experimental conformational behavior, which also cannot be predicted well from conformational energy maps for the disaccharide linkages alone. The crystallographically determined conformation does not appear to be induced by the crystal dimerization, but is rather stable in solution. The build-up of fluctuations along the successive linkages of the oligosaccharide is significant and would be sufficient to prevent branch residues from being located in most crystal structure determinations. Good general agreement between the calculated solution structure and the average structure determined by NMR was found for most of the oligosaccharide linkages.

The structuring of solvent water by sugar solutes is studied using a molecular dynamics (MD) simulation of α- d -glucopyranose in aqueous (SPC) solution. The distribution of water positions actually observed in the MD simulation is compared to the solvent positions expected from a locally-tetrahedral distribution of hydrogen-bonded water molecules around the oxygen atoms. A reasonable correspondence between the observed and predicted hydration sites was found, but with certain deviations resulting from the incommensurate solvation requirements of adjacent functional groups. No evidence was found to support previous theories about sugar hydration which are based upon a supposed coincidence of the sugar structure with an assumed lattice-like model of liquid water. Solvent pair distribution functions were also used to characterize the observed water structuring, and methods of eliminating artificial minima in these distributions resulting from spherical averaging were examined.

Molecular mechanics calculations have been performed for the disaccharide carrabiose, one of the repeat units of β-carrageenan, as a general model for the (14)-linkage in the carrageenans. An adiabatic conformational energy map for this unsulfated molecule was prepared by constrained energy minimization and compared to a previously reported rigid-residue energy map for the sulfated molecule and to a similar adiabatic map for neocarrabiose, the related (13)-linked dimer repeat unit of β-carrageenan. Molecular dynamics simulations of this molecule in vacuo and in an aqueous (TIP3P) solution were calculated, and the observed motions were found to be generally consistent with the vacuum adiabatic energy map. Unlike the case observed in previous simulations of neocarrabiose, little salvation shift in the molecular conformation was observed for carrabiose. From the dynamics, the linkage was observed to be relatively flexible, as has been inferred from experiment on sulfated carrageenan polymers. © 1997 John Wiley & Sons, Inc.

Microcanonical ensemble molecular dynamics simulations have been used to examine the model dependence of the computed three-dimensional structuring which the typical sugar d-xylose imposes on surrounding solvent molecules in aqueous solution. The structuring imposed on water by biological solutes is quite complex, due to the complicated mix of chemical functionalities found in typical biopolymers, and has proven difficult to probe experimentally. Computer simulations have been the principal source of spatially resolved information about the solvent structuring about particular solutes, and previous simulations of this sugar have found configuration-dependent solvent structuring which appears to explain an important experimentally determined physical characteristic of the molecule, its anomeric ratio. Well-defined first and second solvation shells are observed around the sugar molecule with specific locations determined by the arrangement of functional groups in the solute. Here we examine the dependence o...

The method of intramolecular coordination number concentration invariance (ICNCI) is used on neutron diffraction with isotopic substitution (NDIS) measurements of aqueous solutions to separate the intra- and intermolecular contributions to the total intensities. Molecular dynamics simulations of corresponding systems are then used to interpret the ICNCI function. It is found that the ICNCI function (characterized by two concentration measurements) is sensitive specifically to intermolecular association and that the molecular dynamics can successfully replicate this function in the cases of the neutral species xylose and pyridine in aqueous solution. ICNCI functions can also be obtained by the addition of a cosolute (such as adding GdmCl or Gdm2SO4 to pyridine solutions). In that case it is found that molecular dynamics can replicate the ICNCI function for the addition of GdmCl to pyridine, but fails to successfully replicate the same function for the addition of Gdm2SO4. This result implies that the interaction of pyridine with guanidinium sulfate is over-estimated in these MD simulations, and is of significant importance to the use of molecular dynamics simulations to elucidate an atomic level understanding of the Hofmeister series.

Standard molecular dynamics (MD) and free energy simulations have been used to analyze the anomeric equilibrium for d-xylose in aqueous solution. This molecule was selected as a simple model for th...

The details of solution structure have proven difficult to probe experimentally, but computer simulations allow solvent structuring to be examined directly. We report here molecular dynamics (MD) simulations of a series of pentose sugars in solution, describe in detail the three-dimensional structuring which these molecules impose on water, and relate this structuring to the solute molecular topologies. Well-defined first and second solvation shells are observed around the sugar molecules with specific locations determined by the arrangement of functional groups within each solute. Calculated molecular internal energies and solvent interaction energies generally correspond qualitatively with earlier models of sugar energetics based on stability factors. However, pairs of axial hydroxyl groups on the same side of a sugar ring were found to be disfavored by solvation energy, not by internal energy, which is actually more favorable due to intramolecular hydrogen bonding, in accord with both quantum mechanica...

Free energy simulations and standard molecular mechanics calculations have been used to examine the binding specificity of the C-type lectin rat mannose-binding protein. This protein, which is important in inflammation and immunoglobin-independent immune response, recognizes and binds to mannose and high-mannose oligosaccharides but not to galactose. Molecular dynamics simulations were used to estimate the free energy difference between these two sugars in aqueous solution and in the binding site of the protein. While the simulations found mannose to be favored over galactose, interactions with the solvent tended to favor galactose. The calculated binding free energy difference for these two sugars to MBP was 3.1 kcal/mol favoring mannose, approximately twice the experimental value. An estimate of the resolution into components found that enthalpy favored mannose but that entropy favored galactose, a reversal of the situation in solution. From standard MD simulations, the galactose was found to rotate in ...

International audience; The microstructure evolution of confined glucose solutions in silica gels can provide insights into the effect of sugars in protecting living organisms under extreme dehydration conditions. Aqueous silica gels with relatively small pore sizes capable of deforming under changes in environmental conditions are used here as a model system. In situ monitoring of the dehydration process − with and without the presence of sugar molecules − by optical photography, gravimetric measurements, small-angle neutron scattering, and atomic force microscopy reveals that sugar plays a crucial role in the mechanics and protection of the gel. In the absence of sugar, dehydration leads to considerable degradation, whereas the incorporation of large doses of glucose maintains the stability and robustness of the structure. A model is proposed to explain the time dependence of the dehydration process

International audience; The pathway for pyranose ring conformational transitions in both anomers of glucose has been studied using molecular mechanics calculations both in vacuum and in aqueous (SPC/E) solution. The pathway for the transition in vacuum from the 4C1 to the 1C4 chair conformations in a-D-glucopyranose was found to proceed over a low barrier between the 4E and E5 conformers, and centred almost on 4H5, and then downhill through the 1S5 conformation to 1C4. A dead end pathway, with no early barrier, was found to lead to the 5S1 conformation, which thus would represent a kinetic trap impeding interconversion to the opposite chair in vacuum. Hydration was found to significantly lower the transition barriers, and in particular, to make the blocked pathway though 5S1 is feasible at lower temperatures. Transitions between the chair forms for the b-anomer of glucopyranose were in general found to be somewhat more facile, and to exhibit less influence from the presence of solvent.

Molecular dynamics and energy minimization computer modeling calculations have been used to study the conformational behavior of the prototypical triglyceride molecule trilaurin. The energy of an isolated molecule was minimized using both the QuantdCHARMm force field and a newly developed CFF parametrization for comparisons. The crystal structure was found to be a locally stable geometry using CHARMm, but with the CFF potential the structure collapsed into a geometry with C3 symmetry similar to the hypothesized bilayer structure with all three aliphatic chains on the same side of the glycerol backbone. A full molecular dynamics simulation of a trilaurin molecule in aqueous solution, starting in the crystal structure, was also performed. This “tuning fork structure was found to undergo a slow drift in solution toward a more compact geometry, but it was not possible to simulate the system for a sufficient period to determine whether this process was completed or would continue until a geometry similar to the CFF structure was reached. The triglyceride-water interactions were found to be consistent with the behavior expected for a predominantly hydrophobic species containing a polar headgroup consisting of hydrogen-bondaccepting oxygen atoms.

Recent advances in computer speeds now make possible the use of numerical simulations to model directly the relationships between molecular structure and functional properties. Molecular mechanics calculations, particularly molecular dynamics and Monte Carlo simulations, have long been used to study aqueous systems, and have played a crucial role in advancing our understanding of liquid water. It is also possible to use such computer simulations to study the interactions of solvent water with food molecules, which allows the direct theoretical examination of the structural basis for solution properties. We have conducted a series of such studies of several prototypical carbohydrates in aqueous solution. Solvent interactions were found to have significant effects on the conformational behavior of carbohydrates, and different solutes were found to have different effects upon the solvent behavior. The nature of the interaction of water with carbohydrate functional groups was found to depend not only upon the nature of the functional group, but also upon its location in the molecule relative to other functional groups. Hydrogen bonding is particularly important in carbohydrates, and was found to play a complex role in determining solution properties and conformation.

Molecular dynamics simulations were carried out on a concentrated system of β- d -glucopyranose and imidazole molecules in a periodic box of water at 298 K. The purpose of the simulations was to determine whether or not there was any tendency for these two solutes to associate in an aqueous environment, as has previously been observed for other planar functional groups from amino acid side chains, such as the indole group of tryptophan or the phenolic group of tyrosine. A weak stacking interaction between β- d -glucopyranose, as a model for cellulose, and imidazole was indeed observed, with an energy of ∼0.25 kcal/mol per pair, less than kT. Somewhat surprisingly, considerable imidazole self-association into small aggregates (dimers and trimers) was also observed, with binding energies of ∼0.4 kcal/mol per pair, although still less than kT. Considerable non-stacked interactions between glucose and imidazole through hydrogen bonding were also found. These hydrogen bonds primarily involved the N3 atom of imidazole, because the N–H group of N1 was insufficiently polar to compete for water hydrogen bond partners.

A winter flounder antifreeze polypeptide (HPLC-6) has been studied in vacuo and in aqueous solution using molecular dynamics computer simulation techniques. The helical conformation of this polypeptide was found to be stable both in vacuum and in solution. The major stabilizing interactions were found to be the main-chain hydrogen bonds, a salt-bridge interaction, and solute-solvent hydrogen bonds. A significant bending in the middle of the polypeptide chain was observed both in vacuo and in solvent at 300 K. Possible causes of the bending are discussed. From simulations of mutant polypeptide molecules in vacuo, it is concluded that the bend in the native polypeptide was caused by side chain to backbone hydrogen bond competition involving the Thr 24 side chain and facilitated by strains on the helix resulting from the Lys 18-Glu 22 salt bridge.

Molecular dynamics simulations of maltose in two different conformations in vacuum and aqueous (TIP3P) solution have been used to examine the types of hydrogen bonds made by this carbohydrate molecule. Maltose was found to be extensively hydrogen bonded to solvent molecules in aqueous solution, and these hydrogen bonds were found to have potential conformational consequences. The exchange of an intramolecular O2-O3' hydrogen bond found in the crystal structure for hydrogen bonds to solvent was observed to produce significant changes in the solvation of the sugar molecule

Multidimensional potentials of mean force for the interactions in aqueous solution of both anomers of D-glucopyranose with two planar aromatic molecules, indole and para-methyl-phenol, have been calculated using molecular dynamics simulations with umbrella sampling and were subsequently used to estimate binding free energies. Indole and para-methyl-phenol serve as models for the side chains of the amino acids tryptophan and tyrosine, respectively. In all cases, a weak affinity between the glucose molecules and the flat aromatic surfaces was found. The global minimum for these interactions was found to be for the case when the pseudoplanar face of β-D -glucopyranose is stacked against the planar surfaces of the aromatic residues. The calculated binding free energies are in good agreement with both experiment and previous simulations. The multidimensional free energy maps suggest a mechanism that could lend kinetic stability to the complexes formed by sugars bound to sugar-binding proteins.

Molecular dynamics simulations have been used to calculate the potentials of mean force for separating short cellooligomers in aqueous solution as a means of estimating the contributions of hydrophobic stacking and hydrogen bonding to the insolubility of crystalline cellulose. A series of four potential of mean force (pmf) calculations for glucose, cellobiose, cellotriose, and cellotetraose in aqueous solution were performed for situations in which the molecules were initially placed with their hydrophobic faces stacked against one another, and another for the cases where the molecules were initially placed adjacent to one another in a co-planar, hydrogen-bonded arrangement, as they would be in cellulose Ibeta. From these calculations, it was found that hydrophobic association does indeed favor a crystal-like structure over solution, as might be expected. Somewhat more surprisingly, hydrogen bonding also favored the crystal packing, possibly in part because of the high entropic cost for hydrating glucose hydroxyl groups, which significantly restricts the configurational freedom of the hydrogen-bonded waters. The crystal was also favored by the observation that there was no increase in chain configurational entropy upon dissolution, because the free chain adopts only one conformation, as previously observed, but against intuitive expectations, apparently due to the persistence of the intramolecular O3-O5 hydrogen bond.

Molecular dynamics computer simulations have been carried out on aqueous solutions of glucose at concentrations bracketing those previously measured with quasi-elastic neutron scattering (QENS), in order to investigate the motions and interactions of the sugar and water molecules. In addition, QENS measurements have been carried out on fructose solutions to determine whether the effects previously observed for glucose apply to monosaccharide solutions. The simulations indicate a dynamical analogy between higher solute concentration and lower temperature that could provide a key explanation of the bioprotective phenomena observed in many living organisms. The experimental results on fructose solutions show qualitatively similar behavior to the glucose solutions. The dynamics of the water molecules are essentially the same, while the translational diffusion of the sugar molecules is slightly faster in the fructose solutions.

International audience; Molecular dynamics simulations of a 3 molal aqueous solution of d-sorbitol (also called d-glucitol) have been performed at 300 K, as well as at two elevated temperatures to promote conformational transitions. In principle, sorbitol is more flexible than glucose since it does not contain a constraining ring. However, a conformational analysis revealed that the sorbitol chain remains extended in solution, in contrast to the bent conformation found experimentally in the crystalline form. While there are 243 staggered conformations of the backbone possible for this open-chain polyol, only a very limited number were found to be stable in the simulations. Although many conformers were briefly sampled, only eight were significantly populated in the simulation. The carbon backbones of all but two of these eight conformers were completely extended, unlike the bent crystal conformation. These extended conformers were stabilized by a quite persistent intramolecular hydrogen bond between the hydroxyl groups of carbon C-2 and C-4. The conformational populations were found to be in good agreement with the limited available NMR data except for the C-2–C-3 torsion (spanned by the O-2–O-4 hydrogen bond), where the NMR data support a more bent structure.

The calculated free energy difference is the result of near cancelation of two larger, statistically significant contributions, i.e., an intramolecular electrostatic term favoring the α anomer and an intermolecular solute-solvent interaction term favoring the β anomer. This result supports the conjecture that solvation stabilizes the β anomer in water. There is a large difference in the intramolecular contribution to the anomeric equilibrium calculated in solution from the free energy simulation and the gas-phase minimum; this suggests that conformational averaging, modulated by the solvent, is significant even for the internal terms. An examination of the rotamer distribution in the hydroxymethyl side chain shows that the trans, gauche conformer is strongly disfavored in aqueous solution, in accord with experiment

Neutron diffraction experiments were carried out on concentrated aqueous solutions of beryllium chloride at three concentrations: 1.5, 3, and 6 molal. By working with a specific ("null") mixture of heavy water (D2O) and water (H2O), information on the local structure around Be2+ ions was extracted directly. For all three BeCl2 solutions, the results show that the Be2+ ion has a well-defined 4-fold coordination shell that is dominated by oxygen atoms. There is also a relatively small probability (10-15%) that there are direct contacts between Be2+ and Cl- at a distance of approximately 2.2 angstroms. The oxygen atoms of the highly structured Be2+ first hydration shell are found to be situated at 2.6 angstroms apart, and form a pyramidal structure, in agreement with recent MD simulation results. The Cl- ions have approximately seven oxygen atoms (water molecules) in their hydration shells sited at 3.2 angstroms.

Molecular dynamics simulations have been used to study the motions in vacuum of the disaccharide sucrose. Ensembles of trajectories were calculated for each of the five local minimum energy conformations identified in the adiabatic conformational energy mapping of this molecule. The model sucrose molecules were found to exhibit a variety of motions, although the global minimum energy conformation was found to be dynamically stable, and no transitions away from this structure were observed to occur spontaneously. In all but one of these vacuum trajectories, the intramolecular hydrogen bond between residues was maintained, in accord with recent nmr studies of this molecule in aqueous solution. Considerable flexibility of the furanoid ring was found in the trajectories. No "flips" to the opposite puckering for this ring were found in the simulations starting from the global minimum, although such a transition was observed for a trajectory initiated with one of the higher local minimum energy conformations. Overall, the observed structural fluctuations were consistent with the experimental picture of sucrose as a relatively rigid molecule.

The techniques of neutron diffraction with isotopic substitution (NDIS) and molecular dynamics (MD) simulations have been used to examine the rotational conformation of the exocyclic hydroxymethyl group of D-glucopyranose. First order H∕D NDIS experiments were performed on the H6 position in 3m aqueous glucose solutions where the average coherent scattering length of the exchangeable hydrogen atoms was zero (i.e., all correlations between exchangeable hydrogen atoms and other atoms cancel and thus are not present in the scattering data). This H6 experimental result suggests that no single conformation for the C4–C5–C6–O6 dihedral reproduces the observed scattering data well, but that a mixture of the gg and gt conformations, which has been suggested by NMR experiments, gives a reasonable agreement between the MD and experimental data.

Neutron diffraction with isotopic substitution (NDIS) experiments and molecular dynamics (MD) simulations have been used to examine the structuring of solvent around d-glucose in aqueous solution. As expected, no significant tendency for glucose molecules to aggregate was found in either the experiments or the simulation. To the extent that solute pairing does occur as the result of the high concentration, it was found to take place through hydroxyl-hydroxyl hydrogen bonds, in competition with water molecules for the same hydrogen-bonding sites. A detailed analysis of the hydrogen-bonding patterns occurring in the simulations found that the sugar hydroxyl groups are more efficient hydrogen bond donors than acceptors. From the comparison of the MD and NDIS data, it was found that while the modeling generally does a satisfactory job in reproducing the experimental data the force fields may produce sugar rings that are too rigid and thus may require future revisions.

A revised CHARMM-type molecular mechanics potential-energy function has been developed for use in the dynamical simulation of simple carbohydrates in aqueous solution. Atomic charges used in this parameterization were taken to be those previously determined to be appropriate for hydrogen-bonded systems, and the various force-constants were selected by the nonlinear least-squares matching of the calculated normal-mode frequencies and minimum-energy structure to experiment as a function of the parameter set. The new function was found to represent the vibrational spectrum and ring pucker of α- d -glucopyranose as well as previously studied potentials, while incorporating the charges necessary for the simulation of condensed phases. Molecular dynamics simulations of the motions of α- d -glucopyranose in vacuo in both the 1 C 4 and 4 C 1 conformation were conducted, and compared to the results of previous simulations using another potential-energy function. The revised potential function was found to produce a d -glucose molecule less flexible in vacuo than had been previously observed.

Molecular dynamics simulations have been performed on aqueous solutions of two chemically similar nicotinic cholinergic agonists in order to compare their structural and dynamical differences. The cyclic 1,1-dimethyl-4-acetylpiperazinium iodide (HPIP) molecule was previously shown to be a strong agonist for nicotinic acetylcholine receptors (McGroddy et al., 1993), while the acyclic N,N,N,N'-tetramethyl-N'-acetylethylenediamine iodide (HTED) derivative is much less potent. These differences were expected to arise from differences in the solution structures and internal dynamics of the two molecules. HPIP was originally thought to be relatively rigid; however, molecular dynamics simulations suggest that the acetyl portion of the molecule undergoes significant ring dynamics on a psec timescale. The less constrained HTED molecule is relatively rigid, with only one transition observed about any of the major dihedrals in four 100 psec simulations, each started from a different conformation. The average structures obtained from the simulations are very similar to the starting minimized structure in each case, except for the HTED simulation where a single rotation about the N-C-C-N(+) backbone occurred. In each case, HTED had three to five more water molecules in its primary solvation shell than HPIP, indicating that differences in the energetics of desolvation before binding may partially explain the increased potency of HPIP as compared to HTED.

Neutron diffraction experiments and molecular dynamics simulations are used to study the structure of aqueous solutions of two electrolytes: guanidinium sulfate (a mild protein conformation stabilizer) and guanidinium thiocyanate (a powerful denaturant). The MD simulations find the unexpected result that in the Gdm2SO4 solution the ions aggregated into mesoscopic (nanometer-scale) clusters, while no such aggregation is found in the GdmSCN solution. The neutron diffraction studies, the most direct experimental probe of solution structure, provide corroborating evidence that the predicted very strong ion pairing does occur in solutions of 1.5 m Gdm2SO4 but not in 3 m solutions of GdmSCN. A mechanism is proposed as to how this mesoscopic solution structure affects solution denaturant properties and suggests an explanation for the Hofmeister ordering of these solutions in terms of this ion pairing and the ability of sulfate to reverse the denaturant power of guanidinium.