John W. Brady

Additive empirical force field for hexopyranose monosaccharides

We present an all‐atom additive empirical force field for the hexopyranose monosaccharide form of glucose and its diastereomers allose, altrose, galactose, gulose, idose, mannose, and talose. The model is developed to be consistent with the CHARMM all‐atom biomolecular force fields, and the same parameters are used for all diastereomers, including both the α‐ and β‐anomers of each monosaccharide. The force field is developed in a hierarchical manner and reproduces the gas‐phase and condensed‐phase properties of small‐molecule model compounds corresponding to fragments of pyranose monosaccharides. The resultant parameters are transferred to the full pyranose monosaccharides, and additional parameter development is done to achieve a complete hexopyranose monosaccharide force field. Parametrization target data include vibrational frequencies, crystal geometries, solute–water interaction energies, molecular volumes, heats of vaporization, and conformational energies, including those for over 1800 monosaccharide conformations at the MP2/cc‐pVTZ//MP2/6‐31G(d) level of theory. Although not targeted during parametrization, free energies of aqueous solvation for the model compounds compare favorably with experimental values. Also well‐reproduced are monosaccharide crystal unit cell dimensions and ring pucker, densities of concentrated aqueous glucose systems, and the thermodynamic and dynamic properties of the exocyclic torsion in dilute aqueous systems. The new parameter set expands the CHARMM additive force field to allow for simulation of heterogeneous systems that include hexopyranose monosaccharides in addition to proteins, nucleic acids, and lipids.

Carbohydrate solution simulations: Producing a force field with experimentally consistent primary alcohol rotational frequencies and populations

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 (β‐D‐glucose and β‐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 ≈ 66:33:1 and galactose gg:gt:tg ≈ 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 β‐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.

A revised potential-energy surface for molecular mechanics studies of carbohydrates

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 alpha-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 alpha-D-glucopyranose in vacuo in both the 1C4 and 4C1 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.

Reversible dehydration of trehalose and anhydrobiosis: from solution state to an exotic crystal?

Abstract Physico-chemical properties of the trehalose–water system are reviewed with special reference to the transformations that may shed light on the mechanism of trehalose bio-protection. Critical analysis of solution thermodynamics is made in order to scrutinize trehalose properties often called ‘anomalous’ and to check the consistency of literature results. Discussion on the conversion between the solid state polymorphic forms is given, with a special emphasis of the transformations involving the newly identified anhydrous crystalline form of α,α-trehalose, TREα. This exotic crystal is almost ‘isomorphous’ with the dihydrate crystal structure, and possesses the unique feature of reversibly absorbing water to produce the dihydrate, without changing the main structural features. The reversible process could play a functional role in the well-known ability of this sugar to protect biological structures from damage during desiccation. The final aim of the paper is to add some new insights into and to reconcile previous hypotheses for the peculiar ‘in vivo’ action of trehalose.

Simulation studies of the insolubility of cellulose

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.

Comparison of Cellulose Iβ Simulations with Three Carbohydrate Force Fields

Molecular dynamics simulations of cellulose have recently become more prevalent due to increased interest in renewable energy applications, and many atomistic and coarse-grained force fields exist that can be applied to cellulose. However, to date no systematic comparison between carbohydrate force fields has been conducted for this important system. To that end, we present a molecular dynamics simulation study of hydrated, 36-chain cellulose Iβ microfibrils at room temperature with three carbohydrate force fields (CHARMM35, GLYCAM06, and Gromos 45a4) up to the near-microsecond time scale. Our results indicate that each of these simulated microfibrils diverge from the cellulose Iβ crystal structure to varying degrees under the conditions tested. The CHARMM35 and GLYCAM06 force fields eventually result in structures similar to those observed at 500 K with the same force fields, which are consistent with the experimentally observed high-temperature behavior of cellulose I. The third force field, Gromos 45a4, produces behavior significantly different from experiment, from the other two force fields, and from previously reported simulations with this force field using shorter simulation times and constrained periodic boundary conditions. For the GLYCAM06 force field, initial hydrogen-bond conformations and choice of electrostatic scaling factors significantly affect the rate of structural divergence. Our results suggest dramatically different time scales for convergence of properties of interest, which is important in the design of computational studies and comparisons to experimental data. This study highlights that further experimental and theoretical work is required to understand the structure of small diameter cellulose microfibrils typical of plant cellulose.

Observations concerning the treatment of long‐range interactions in molecular dynamics simulations

Molecular dynamics simulations of pure water employing two different empirical water models have been used to study the effects of different methods for truncation of long‐range interactions in molecular mechanics calculations. As has been observed previously in integral equation studies, “shifting” these interactions on an atom‐by‐atom basis was found to produce artificial structuring in the water and affect diffusion rates. In cases where some form of short‐range truncation must be used, the ST2 switching function applied on a group‐by‐group basis was found to be the most realistic procedure. If atom‐based shifting must be employed, a cutoff distance greater than or equal to 12.0 Å was found to be required to produce realistic results.

Specificity of Ion−Protein Interactions: Complementary and Competitive Effects of Tetrapropylammonium, Guanidinium, Sulfate, and Chloride Ions

The interactions of ions with a model peptide (a single melittin alpha-helix) in solutions of tetrapropylammonium sulfate or guanidinium chloride were examined by molecular dynamics simulations. The tetrapropylammonium cation shares the geometrical property of essentially flat faces with the previously examined guanidinium cation, and it was found that that this geometry leads to a strong preference for tetrapropylammonium to interact in a similar stacking-type fashion with flat nonpolar groups such as the indole side chain of tryptophan. In contrast to guanidinium, however, tetrapropylammonium does not exhibit strong ion pairing or clustering with sulfate counterions in the solution. Sulfate was found to interact almost exclusively and strongly with the cationic groups of the peptide, such that, already in a 0.1 m solution of tetrapropylammonium sulfate, the 6+ charge of the peptide is effectively locally neutralized. In combination with previous simulations, neutron scattering studies, and experiments on the conformational stability of model peptides, the present results suggest that the Hofmeister series can be explained in higher detail by splitting ions according to the effect they have on hydrogen bonding, salt bridges, and hydrophobic interactions in the protein and how these effects are altered by the counterion.

Classical dynamics study of intramolecular energy flow in benzene

The flow of energy from highly excited CH overtones in benzene is investigated by quasiclassical trajectory methods for atomic motions restricted to the molecular plane. Various initial conditions and potential‐energy surfaces (harmonic and anharmonic) are examined. The results are in accord with the rapid energy transfer rates observed in experiments. Comparisons are made with other theoretical studies.

Computational simulations of the Trichoderma reesei cellobiohydrolase I acting on microcrystalline cellulose Iβ: the enzyme-substrate complex.

Cellobiohydrolases are the dominant components of the commercially relevant Trichoderma reesei cellulase system. Although natural cellulases can totally hydrolyze crystalline cellulose to soluble sugars, the current enzyme loadings and long digestion times required render these enzymes less than cost effective for biomass conversion processes. It is clear that cellobiohydrolases must be improved via protein engineering to reduce processing costs. To better understand cellobiohydrolase function, new simulations have been conducted using charmm of cellobiohydrolase I (CBH I) from T.reesei interacting with a model segment (cellodextrin) of a cellulose microfibril in which one chain from the substrate has been placed into the active site tunnel mimicking the hypothesized configuration prior to final substrate docking (i.e., the +1 and +2 sites are unoccupied), which is also the structure following a catalytic bond scission. No tendency was found for the protein to dissociate from or translate along the substrate surface during this initial simulation, nor to align with the direction of the cellulose chains. However, a tendency for the decrystallized cellodextrin to partially re-anneal into the cellulose surface hints that the arbitrary starting configuration selected was not ideal.