Crystallization tendencies of modelled Lennard-Jones liquids with different attractions.

Molecular dynamics simulations are performed on simple models composed of monoatomic Lennard-Jones atoms for which the repulsive interaction is the same but the attractive part is tuned. We investigate the precise role of the attractive part of the interaction potential on different structural, dynamical, and thermodynamical properties of these systems in the liquid and crystalline states. It includes crystallization trends for which the main physical ingredients involved have been computed: the diffusion coefficient, the Gibbs energy difference between the liquid and the crystalline state, and the crystal-liquid interfacial free energy. Results are compared with predictions from the classical nucleation theory including transient and steady-state regimes at moderate and deeper undercooling. The question of the energetic and entropic impact of the repulsive and attractive part of the interaction potential towards crystallization is also addressed.

A comparative study of ibuprofen and ketoprofen glass-forming liquids by molecular dynamics simulations.

In this paper, structural and dynamical properties of ibuprofen and ketoprofen glass-forming liquids have been investigated by means of molecular dynamics simulations. Molecular mobility of both materials is analyzed with respect to the different inter-molecular linear/cyclic hydrogen bonding associations. For ibuprofen, the dominant organization is found to be composed of small hydrogen bonding aggregates corresponding to cyclic dimers through the carboxyl group. For ketoprofen, the propensity of cyclic dimers is significantly reduced by the formation of hydrogen bonds with the ketone oxygen of the molecule altering the hydrogen bond (HB) associating structures that can be formed and thus molecular dynamics. The issue of the presence/absence of the peculiar low frequency Debye-type process in dielectric relaxation spectroscopy (DRS) data in these materials is addressed. Results obtained from simulations confirm that the Debye process originates from the internal cis-trans conversion of the -COOH carboxyl group. It is shown that the specific intermolecular HB structures associated to a given profen control the main dynamical features of this conversion, in particular its separation from the α-process, which make it detectable or not from DRS. For ibuprofen, the possible role of the -CCCO torsion motion, more "local" than the -COOH motion since it is less influenced by the intermolecular HBs, is suggested in the microscopic origin of the quite intense secondary γ-relaxation process detected from DRS.

Predictive Calculation of the Crystallization Tendency of Model Pharmaceuticals in the Supercooled State from Molecular Dynamics Simulations.

Molecular dynamics (MD) simulations were used to perform a comparative study of the crystallization tendency from the melt of two model pharmaceutical compounds: felodipine and nifedipine. Two crystalline polymorphs of nifedipine (N(α), N(ß)) and felodipine (FI, FII) have been studied. Calculations were performed on liquid and crystal systems separately in order to determine their main physical properties (diffusivity, density, and enthalpy). A fair agreement was found between the simulation and the known experimental data confirming the ability of the force field GAFF to reproduce accurately the experimental data for both compounds. Simulations of the crystal-liquid interface enabled the determination of the melting temperature and the interfacial free energy of the different polymorphs. Guided by the classical nucleation theory (CNT) predictions and different growth mechanism models (normal, two-dimensional, and screw dislocation), the nucleation and growth rates have been determined. The present investigation particularly raises the very important role of the solid-liquid interfacial free energy and its interplay with the driving force during the crystallization. The origin of the higher crystallization tendency of nifedipine with respect to felodipine is discussed from the present computed kinetic and thermodynamical factors.

Molecular mobility of amorphous S-flurbiprofen: a dielectric relaxation spectroscopy approach.

Amorphous S-flurbiprofen was obtained by the melt quench/cooling method. Dielectric measurements performed in the isochronal mode, conventional and temperature modulated differential scanning calorimetry (TMDSC) studies showed a glass transition, recrystallization, and melting. The different parameters characterizing the complex molecular dynamics of amorphous S-flurbiprofen that can have influence on crystallization and stability were comprehensively characterized by dielectric relaxation spectroscopy experiments (isothermal mode) covering a wide temperature (183 to 408 K) and frequency range (10(-1) to 10(6) Hz): width of the α-relaxation (ßKWW), temperature dependence of α-relaxation times (τα), fragility index (m), relation of the α-relaxation with the ß-secondary relaxation, and the breakdown of the Debye-Stokes-Einstein (DSE) relationship between the structural relaxation time and dc-conductivity (σdc) at deep undercooling close to Tg. The ß-relaxation, observed in the glassy as well as in the supercooled state was identified as the genuine Johari-Goldstein process, attributed to localized motions and regarded as the precursor of the α-relaxation as suggested in the coupling model. A separation of about 6 decades between the α- and ß-relaxation was observed at Tg; this decoupling decreased on increasing temperature, and both processes merged at Tαß = 295 K. The temperature dependence of the α-relaxation time, τα, was described by two Vogel-Fulcher-Tammann-Hesse equations, which intercept at a crossover temperature, TB = 290 K, close to the splitting temperature between the α- and ß-relaxation. From the low temperature VFTH equation, a Tg(DRS) = 265.2 was estimated (at τα =100 s) in good agreement with the calorimetric value (Tg,onset,TMDSC = 265.6 K), and a fragility or steepness index m = 113 was calculated allowing to classify S-flurbiprofen as a fragile glass former. The α-relaxation spectra were found to be characterized by a relatively large degree of nonexponentiality (ßKWW = 0.52). A breakdown of the DSE log10 σdc - log10 τ relation was observed revealing an enhancement of translational ionic motions in comparison with the orientational molecular motions as the glass transition temperature Tg is approached from above.

The non-Gaussian dynamics of glycerol.

We have combined incoherent quasielastic neutron scattering experiments and atomistic molecular simulations to investigate the microscopic dynamics of glycerol moving away from the hydrodynamic limit. We relate changes in the momentum transfer (Q) dependence of the relaxation time to distinct changes of the single-particle dynamics. Going from small to large values of Q, a first crossover at about 0.5 Å(-1) is related to the coupling of the translational diffusion dynamics to the non-Debye structural relaxation, while the second crossover at a Q-value near the main diffraction peak is associated with the Gaussian to non-Gaussian crossover of the short-time molecular dynamics, related to the decaging processes. We offer an unprecedented extension of previous studies on polymeric systems towards the case of the typical low-molecular-weight glass-forming system glycerol.

Debye process in Ibuprofen glass-forming liquid: insights from molecular dynamics simulation.

By means of molecular dynamics simulations, dynamical properties of racemic ibuprofen glass-forming liquid are investigated at different temperatures from 360 to 500 K. The origin of the peculiar low amplitude Debye-type relaxation observed experimentally by dielectric relaxation spectroscopy is addressed (Bras, A. R.; Noronha, J. P.; Antunes, A. M. M.; Cardoso, M. M.; Schonhals, A.; Affouard, F.; Dionisio, M.; Correia, N. T. J. Phys. Chem. B 2008, 112, 11087). Single and total dipolar autocorrelation functions are calculated. It is found that the behavior of the total dipole correlation is dominated at short and long times by the single function. It mainly originates from the antiparallel dipoles correlations in agreement with a value of the Kirkwood correlation factor slightly smaller than unity. The simulation suggests that the long time Debye-type decay of the dipole-dipole correlation is dominated by the internal cis-trans conversion of the O=C-O-H group coupled to the change of the intermolecular linear/cyclic HB structures. The overall rotation of the molecules is about 1-2 decades faster than the cis to trans transformation, so all the O=C-O-H group environments are equal on average. The effective rotational potential energy barriers of the O=C-O-H groups due to the surroundings are thus averaged and dipolar relaxation follows a simple Debye law. It is found that cyclic dimers inhibit the cis to trans conversion unlike the linear dimers and trimers which favor this conversion and stabilize the trans isomer. It is well in line with the very low amplitude of the dielectric strength associated with the Debye relaxation observed experimentally and its increase when the liquid is maintained isothermally above the melting temperature since this amplitude mainly relates to the low fraction of ibuprofen molecules in the trans conformation. A comparison is made with the Debye-type relaxation found in microstructured monohydroxy alcohols.

Molecular dynamics simulation of nanoconfined glycerol.

We present results from molecular dynamics simulations of liquid glycerol confined in a realistic model of a cylindrical silica nanopore. The influence of the hydrophilic surface and the geometrical confinement on the structure, hydrogen-bond lifetime, rotational and translational molecular dynamics are analysed. Layering and dynamical heterogeneities are induced by confinement. These features share some similarities with previous observations in simpler van der Waals glass-forming liquids. In addition, the specificity of glycerol as an associated liquid shows up in confinement by the formation of interfacial hydrogen bonds and some modifications of the in-pore hydrogen-bonding network. Confinement is also seen to influence the relaxation dynamics and the glassy behaviour in the supercooled state. These phenomena revealed by molecular simulation are important inputs for a better understanding of the many recent experimental results on confined glycerol and more generally for the possible manipulation of associated liquids in porous or fluidic devices.

Mixing effects in glass-forming Lennard-Jones mixtures.

Mixing effects have been investigated from molecular dynamics simulations at constant number of particles, volume, and temperature on the Kob-Andersen glass-forming Lennard-Jones atomic mixture A(x)B(1-x) for 0 < or = x < or = 1 compositions. Upon cooling, crystallization is observed for x < or = 0.5 and x > or = 0.9 compositions. The crystalline states can be described by a quite complex coexistence of voids (x < or = 0.5), point defects, and one or two crystal structures which were characterized and found identical to those reported by Fernandez and Harrowell [Phys. Rev. E 67, 011403 (2003)] from energy minimization. Amorphization is also seen at 0.6 < or = x < or = 0.8 compositions and it is suggested that both crystal structures, CsCl and fcc-hcp, do not compete at these compositions since only one type of crystalline seed is found in the liquid, either fcc/hcp or CsCl. A significant decrease in the diffusion constants for both A and B particles is also seen above x(A) approximately = 0.5. The problem of the extraordinary stability of the model against crystallization is discussed.

Low-frequency vibrational properties of lysozyme in sugar aqueous solutions: a Raman scattering and molecular dynamics simulation study.

The low-frequency (omega<400 cm(-1)) vibrational properties of lysozyme in aqueous solutions of three well-known protecting sugars, namely, trehalose, maltose, and sucrose, have been investigated by means of complementary Raman scattering experiments and molecular dynamics simulations. The comparison of the Raman susceptibility chi(")(omega) of lysozyme/water and lysozyme/sugar/water solutions at a concentration of 40 wt % with the chi(") of dry lysozyme suggests that the protein dynamics mostly appears in the broad peak around 60-80 cm(-1) that reflects the vibrations experienced by atoms within the cage formed by their neighbors, whereas the broad shoulder around 170 cm(-1) mainly stems from the intermolecular O-H...O stretching vibrations of water. The addition of sugars essentially induces a significant high frequency shift and intensity reduction of this band that reveal a slowing down of water dynamics and a distortion of the tetrahedral hydrogen bond network of water, respectively. Furthermore, the lysozyme vibrational densities of states (VDOS) have been determined from simulations of lysozyme in 37-60 wt % disaccharide aqueous solutions. They exhibit an additional broad peak around 290 cm(-1), in line with the VDOS of globular proteins obtained in neutron scattering experiments. The influence of sugars on the computed VDOS mostly appears on the first peak as a slight high-frequency shift and intensity reduction in the low-frequency range (omega<50 cm(-1)), which increase with the sugar concentration and with the exposition of protein residues to the solvent. These results suggest that sugars stiffen the environment experienced by lysozyme atoms, thereby counteracting the softening of protein vibrational modes upon denaturation, observed at high temperature in the Raman susceptibility of the lysozyme/water solution and in the computed VDOS of unfolded lysozyme in water. Finally, the Raman susceptibility of sugar/water solutions and the calculated VDOS of water in the different lysozyme solutions confirm that sugars induce a significant strengthening of the hydrogen bond network of water that may stabilize proteins at high temperatures.

Characterization of molecular motions in biomolecular systems by elastic incoherent neutron scattering.

In the present work the role played by the instrumental resolution function in elastic incoherent neutron scattering (EINS) experiment is discussed. An important result consists in the definition of an equivalent time t(*), which depends both on the characteristic system time and on the resolution time, for which the spatial Fourier transform of EINS intensity profile and the self-distribution function (SDF) evaluated at t=t(*) are proportional. Then the equivalent time t(*) is introduced in the SDF procedure, an operational recipe for the mean square displacement determination. The new revised procedure is applied on data of myoglobin in trehalose dry environment and of hydrated homologous disaccharides (sucrose and trehalose).

How do trehalose, maltose, and sucrose influence some structural and dynamical properties of lysozyme? Insight from molecular dynamics simulations.

The influence of three well-known disaccharides, namely, trehalose, maltose, and sucrose, on some structural and dynamical properties of lysozyme has been investigated by means of molecular dynamics computer simulations in the 37-60 wt % concentration range. The effects of sugars on the protein conformation are found to be relatively weak, in agreement with the preferential hydration of lysozyme. Conversely, sugars seem to increase significantly the relaxation times of the protein. These effects are shown to be correlated to the fractional solvent accessibilities of lysozyme residues and further support the slaving of protein dynamics. Moreover, a significant increase in the relaxation times of lysozyme, sugars, and water molecules is observed within the studied concentration range and may result from the percolation of the hydrogen-bond network of sugar molecules. This percolation appears to be of primary importance to explain the influence of sugars on the dynamical properties of lysozyme and water.

Analysis of sugar bioprotective mechanisms on the thermal denaturation of lysozyme from Raman scattering and differential scanning calorimetry investigations.

Sugar-induced thermostabilization of lysozyme was analyzed by Raman scattering and modulated differential scanning calorimetry investigations, for three disaccharides (maltose, sucrose, and trehalose) characterized by the same chemical formula (C(12)H(22)O(11)). This study shows that trehalose is the most effective in stabilizing the folded secondary structure of the protein. The influence of sugars on the mechanism of thermal denaturation was carefully investigated by Raman scattering experiments carried out both in the low-frequency range and in the amide I band region. It was determined that the thermal stability of the hydrogen-bond network of water, highly dependent on the presence of sugars, contributes to the stabilization of the native tertiary structure and inhibits the first stage of denaturation, that is, the transformation of the tertiary structure into a highly flexible state with intact secondary structure. It was found that trehalose exhibits exceptional capabilities to distort the tetra-bonded hydrogen-bond network of water and to strengthen intermolecular O-H interactions responsible for the stability of the tertiary structure. Trehalose was also observed to be the best stabilizer of the folded secondary structure, in the transient tertiary structure, leading to a high-temperature shift of the unfolding process (the second stage of denaturation). This was interpreted from the consideration that the transient tertiary structure is less flexible and inhibits the solvent accessibility around the hydrophobic groups of lysozyme.

Evidence of a two-stage thermal denaturation process in lysozyme: a Raman scattering and differential scanning calorimetry investigation.

Raman spectroscopy (in the low-frequency range and the amide I band region) and modulated differential scanning calorimetry investigations have been used to analyze temperature-induced structural changes in lysozyme dissolved in 1H2O and 2H2O in the thermal denaturation process. Low-frequency Raman data reveal a change in tertiary structure without concomitant unfolding of the secondary structure. Calorimetric data show that this structural change is responsible for the configurational entropy change associated with the strong-to-fragile liquid transition and correspond to about 1/3 of the native-denaturated transition enthalpy. This is the first stage of the thermal denaturation which is a precursor of the secondary structure change and is determined to be strongly dependent on the stability of the hydrogen-bond network in water. Low-frequency Raman spectroscopy provides information on the flexibility of the tertiary structure (in the native state and the transient folding state) in relation to the fragility of the mixture. The unfolding of the secondary structure appears as a consequence of the change in the tertiary structure and independent of the solvent. Protein conformational stability is directly dependent on the stability of the native tertiary structure. The structural transformation of tertiary structure can be detected through the enhanced 1H/2H exchange inhibited in native proteins. Taking into account similar features reported in the literature observed for different proteins it can be considered that the two-stage transformation observed in lysozyme dissolved in water is a general mechanism for the thermal denaturation of proteins.

Onset of slow dynamics in difluorotetrachloroethane glassy crystal.

Complementary neutron spin-echo and x-ray experiments and molecular-dynamics simulations have been performed on difluorotetrachloroethane (CFCl2-CFCl2) glassy crystal. Static, single-molecule reorientational dynamics and collective dynamics properties are investigated. Our results confirm the strong analogy between molecular liquids and plastic crystals. The orientational disorder is characterized at different temperatures and a change in the nature of rotational dynamics is observed. A careful check of the rotational diffusion model is performed using self-angular correlation functions Cl with high l values and compared to results obtained on molecular liquids composed of A-B dumbbells. Below the crossover temperature at which slow dynamics emerge, we show that some scaling predictions of the mode coupling theory hold and that alpha-relaxation times and nonergodicity parameters are controlled by the nontrivial static correlations.

Analogy of the slow dynamics between the supercooled liquid and supercooled plastic crystal states of difluorotetrachloroethane.

Slow dynamics of difluorotetrachloroethane in both supercooled plastic crystal and supercooled liquid states have been investigated with molecular dynamics simulations. The temperature and wave-vector dependence of collective dynamics in both states are probed using coherent dynamical scattering functions S (Q,t). Our results confirm the strong analogy between molecular liquids and plastic crystals for which alpha-relaxation times and nonergodicity parameters are controlled by the nontrivial static correlations S (Q), as predicted by the mode coupling theory.

How homogeneous are the trehalose, maltose, and sucrose water solutions? An insight from molecular dynamics simulations.

The structural properties resulting from the reciprocal influence between water and three well-known homologous disaccharides, namely, trehalose, maltose, and sucrose, in aqueous solutions have been investigated in the 4-66 wt % concentration range by means of molecular dynamics computer simulations. Hydration numbers clearly show that trehalose binds to a larger number of water molecules than do maltose or sucrose, thus affecting the water structure to a deeper extent. Two-dimensional radial distribution functions of trehalose solutions definitely reveal that water is preferentially localized at the hydration sites found in the trehalose dihydrate crystal, this tendency being enhanced when increasing trehalose concentration. Over a rather wide concentration range (4-49 wt %), the fluctuations of the radius of gyration and of the glycosidic dihedral angles of trehalose indicate a higher flexibility with respect to maltose and sucrose. At sugar concentrations between 33 and 66 wt %, the mean sugar cluster size and the number of sugar-sugar hydrogen bonds formed within sugar clusters reveal that trehalose is able to form larger clusters than sucrose but smaller than maltose. These features suggest that trehalose-water mixtures would be more homogeneous than the two others, thus reducing both desiccation stresses and ice formation.

Is there something of mode coupling theory in orientationally disordered crystals?

Molecular dynamics simulations have been performed on the orientationally disordered crystal chloroadamantane. We stress that universal behavior, relatively well described by the mode coupling theory, is shared by systems whose dynamics are almost completely controlled by translations or rotations. This investigation also shows the existence of a second remarkable dynamical crossover at the temperature Tx>Tc, consistent with a previous NMR and molecular dynamics study [F. Affouard et al., Europhys. Lett. 53, 611 (2001)]. This allows us to support clearly the existence of a "landscape-influenced" regime as recently proposed [S. Sastry et al., Nature 393, 554 (1998)].