We present a CHARMM Carbohydrate Solution Force Field (CSFF) suitable for nanosecond molecular dynamics computer simulations. The force field was derived from a recently published sugar parameter set.1 Dihedral angle parameters for the primary alcohol as well as the secondary hydroxyl groups were adjusted. Free energy profiles of the hydroxymethyl group for two monosaccharides (beta-D-glucose and beta-D-galactose) were calculated using the new parameter set and compared with similar force fields. Equilibrium rotamer populations obtained from the CSFF are in excellent agreement with NMR data (glucose gg:gt:tg approximately 66:33:1 and galactose gg:gt:tg approximately 4:75:21). In addition, the primary alcohol rotational frequency is on the nanosecond time scale, which conforms to experimental observations. Equilibrium population distributions of the primary alcohol conformers for glucose and galactose are reached within 10 nanoseconds of molecular dynamics simulations. In addition, gas phase vibrational frequencies computed for beta-D-glucose using this force field compare well with experimental frequencies. Carbohydrate parameter sets that produce both conformational energies and rotational frequencies for the pyranose primary alcohol group that are consistent with experimental observations should allow for increased accuracy in modeling the flexibility of biologically important (1-6)-linked saccharides in solution.

Several blood-feeding organisms, including the malaria parasite detoxify haem released from host haemoglobin by conversion to the insoluble crystalline ferriprotoporphyrin IX dimer known as haemozoin. To date the mechanism of haemozoin formation has remained unknown, although lipids or proteins have been suggested to catalyse its formation. We have found that beta-haematin (synthetic haemozoin) forms rapidly under physiologically realistic conditions near octanol/water, pentanol/water and lipid/water interfaces. Molecular dynamics simulations show that a precursor of the haemozoin dimer forms spontaneously in the absence of the competing hydrogen bonds of water, demonstrating that this substance probably self-assembles near a lipid/water interface in vivo.

The puckered conformations of furanose and pyranose carbohydrate rings are central to analyzing the action of enzymes on carbohydrates. Enzyme reaction mechanisms are generally inaccessible to experiments and so have become the focus of QM(semiempirical)/MM simulations. We show that the complete free energy of puckering is required to evaluate the accuracy of semiempirical methods used to study reactions involving carbohydrates. Interestingly, we find that reducing the free energy space to lower dimensions results in near meaningless minimum energy pathways. We analyze the furanose and pyranose free energy pucker surfaces and volumes using AM1, PM3, PM3CARB-1, and SCC-DFTB. A comparison with DFT optimized structures and a HF free energy surface reveals that SCC-DFTB provides the best semiempirical description of five- and six-membered carbohydrate ring deformation.

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We describe the implementation of an adaptive umbrella sampling method, making use of the weighted histogram analysis method, for computing multidimensional potential of mean force for chemical reaction in solution. The approach is illustrated by investigating the effect of aqueous solution on the free energy surface for the proton transfer reaction of [H(3)N-H-NH(3)](+) using a combined quantum mechanical and molecular mechanical AM1/TIP3P potential.

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We report the results of molecular dynamics (MD) simulations compared with NMR relaxation experiments for maltose and isomaltose. The (Φ,Ψ) adiabatic map for maltose shows a single principal energy well, while the (Φ,Ψ,Ω) map of isomaltose reveals multiple low energy minima separated by significant barriers (9 kcal/mol) in some cases. The greater accessible conformational space of the α(1→6) linkage appears to make it more flexible as compared with the α(1→4) linkage, especially in the presence of water. Correlation times for glycosidic dihedral angle fluctuations are significantly shorter in the case of isomaltose. While the generalized order parameters calculated from the simulations do not show a large difference in the spatial restriction of the motion, they are nonetheless generally lower for isomaltose. The time scales of the overall rotational motion (τM) and the local molecular motion (τe) are similar for both maltose and isomaltose. This makes reliable estimates of order parameters from experimental relaxation data (using the model-free formalism) unfeasible. We were, however, able to show that T 1 relaxation times calculated from the MD data agree well with the experimental values. As a further measure of solution flexibility, three-dimensional water distributions were calculated about each disaccharide. These demonstrate that the more rigid maltose solute causes the water to adopt a more localized structure about it. Because of its extended structure, isomaltose appears to make a greater number of hydrogen bonds to water.

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 R(1f4)-linked dimer of D-xylopyranose (4-O-R-D-xylopyranosyl-R-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 minimumenergy 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. Unfortunately, the results reaffirm the dependence of hydration effects upon the specific details of each molecule's chemical structure, making the application of simple general models for hydration more difficult.