Tuning molecular dynamics by hydration and confinement: antiplasticizing effect of water in hydrated prilocaine nanoclusters.

In glass-forming substances, the addition of water tends to produce the effect of lowering the glass transition temperature, Tg. In a previous work by some of us (Ruiz et al., Sci. Rep., 2017, 7, 7470) we reported on a rare anti-plasticizing effect of water on the molecular dynamics of a simple molecular system, the pharmaceutically active prilocaine molecule, for which the addition of water leads to an increase of Tg. In the present work, we study pure and hydrated prilocaine confined in 0.5 nm and 1 nm pore size molecular sieves, and carry out a comparison with the bulk compounds in order to gain a better understanding of the microscopic mechanisms that result in this rare effect. We find that the Tg of the drug under nanometric confinement can be lower than the bulk value by as much as 17 K. Through the concurrent use of differential scanning calorimetry and broadband dielectric spectroscopy we are able to observe the antiplasticizing effect of water in prilocaine also under nanometric confinement, finding an increase of Tg of up to almost 6 K upon hydration. The extension of our analysis to nanoconfined systems provides a plausible explanation for the very uncommon antiplasticizing effect, based on the formation of water-prilocaine molecular complexes. Moreover, this study deepens the understanding of the behavior of drugs under confinement, which is of relevance not only from a fundamental point of view, but also for practical applications such as drug delivery.

Reply to the 'Comment on "On the positional and orientational order of water and methanol around indole: a study on the microscopic origin of solubility" Phys. Chem. Chem. Phys., 2018, 20, DOI: '.

In his comment on a recent publication by us, G. Graziano claims that solubility differences of indole in methanol and water can be rationalized by the reversible work needed to create a cavity in the solvent of the size of the solute, in this case indole. This quantity, he argues, is closely related to the solvent accessible surface area, which is greater for methanol compared with water, thus making indole more soluble in the former solvent. G. Graziano asserts that it is this property which is responsible for the large difference between the solubilities of indole in methanol and water. Further, G. Graziano claims that the differences in excess entropies and in distance distribution functions of indole in methanol and water and in methanol and water as a cosolvent found in our original work (Henao, et al., Phys. Chem. Chem. Phys., 2016, 18, 23006) are too "small" to be able to account for the differences in solubility of the indole molecule. We show in this work that the differences found by us are not small, by displaying some selected distance distribution functions in an alternative way to that described in our original paper. In fact we conclude that the differences in these functions are quantitatively greater than those found by Graziano in his comment. Secondly, we show in this reply that although the increase of the solvent accessible surface area may rationalize the differences in the indole-methanol and indole-water binary systems, and thus the work required for cavity creation, it is insufficient to fully account for the increase of indole solubility in water by the addition of very small quantities of methanol in the ternary system indole-methanol-water. In other words, as stated in our original paper, methanol is actively changing the solvation shell and not just passively increasing the solvent accessible surface area around indole. As a result of these additional analyses, we conclude that our work on the solvation differences of indole in water and methanol successfully captures differences in the solvation shells of both solvents around indole in both binary and ternary systems. Finally, while we do agree that Graziano's calculations are able to capture the role of cavity creation to explain differences in solubility, we think that our results concerning the quantification of changes in molecular interaction should be added to the calculations suggested by him to lead to a full description of the solubility.

Hydrogen Bond Length as a Key To Understanding Sweetness.

Neutron diffraction experiments have been performed to investigate and compare the structure of the hydration shell of three monosaccharides, namely, fructose, glucose, and mannose. It is found that despite their differences with respect to many thermodynamical quantities, bioprotective properties against environmental stresses, and taste, the influence of these monosaccharides on the bulk water solvent structure is virtually identical. Conversely, these sugars interact with the neighboring water molecules by forming H bonds of different length and strength. Interestingly, the sweetness of these monosaccharides, along with that of the disaccharide trehalose, is correlated with the length of these H bonds. This suggests that the small differences in stereochemistry between the different sugars determine a relevant change in polarity, which has a fundamental impact on the behavior of these molecules in vivo.

Structure of aqueous proline via parallel tempering molecular dynamics and neutron diffraction.

The structure of aqueous L-proline amino acid has been the subject of much debate centering on the validity of various proposed models, differing widely in the extent to which local and long-range correlations are present. Here, aqueous proline is investigated by atomistic, replica exchange molecular dynamics simulations, and the results are compared to neutron diffraction and small angle neutron scattering (SANS) data, which have been reported recently (McLain, S.; Soper, A.; Terry, A.; Watts, A. J. Phys. Chem. B 2007, 111, 4568). Comparisons between neutron experiments and simulation are made via the static structure factor S(Q) which is measured and computed from several systems with different H/D isotopic compositions at a concentration of 1:20 molar ratio. Several different empirical water models (TIP3P, TIP4P, and SPC/E) in conjunction with the CHARMM22 force field are investigated. Agreement between experiment and simulation is reasonably good across the entire Q range although there are significant model-dependent variations in some cases. In general, agreement is improved slightly upon application of approximate quantum corrections obtained from gas-phase path integral simulations. Dimers and short oligomeric chains formed by hydrogen bonds (frequently bifurcated) coexist with apolar (hydrophobic) contacts. These emerge as the dominant local motifs in the mixture. Evidence for long-range association is more equivocal: No long-range structures form spontaneously in the MD simulations, and no obvious low-Q signature is seen in the SANS data. Moreover, associations introduced artificially to replicate a long-standing proposed mesoscale structure for proline correlations as an initial condition are annealed out by parallel tempering MD simulations. However, some small residual aggregates do remain, implying a greater degree of long-range order than is apparent in the SANS data.

Glucose and Mannose: A Link between Hydration and Sweetness.

Glucose and mannose have a different degree of sweetness, implying different affinity to the sweet taste receptor. While the receptor structure is still undefined, there are several geometrical models for their binding mechanism. A detailed study of the hydration structure of sugars with known degree of sweetness is bound to provide information on the accuracy of such models. Our neutron diffraction study on the hydration of glucose and mannose show that both α- and ß-glucose form strong hydrogen bonds with water, and that the steric hindrance of their first hydration shell matches the receptor geometrical model. The α-anomer of mannose has a similar, well-defined first hydration shell, but with fewer and weaker hydrogen bonds compared to glucose. Conversely, the hydration shell of ß-mannose (reported as bitter) does not match the receptor geometrical model. These findings suggest a link between the hydration shell of sugars and their degree of sweetness.

Water and trehalose: how much do they interact with each other?

The observation made by early naturalists that some organisms could tolerate extreme environmental condisions and "enjoy the advantage of real resurrection after death" [ Spallanzani , M. Opuscules de Physique Animale et Vegetale 1776 (translated from Italian by Senebier , J. Opuscules de Physique Animale et Vegetale 1787 , 2 , 203 - 285 )] stimulated research that still continues to this day. Cryptobiosis, the ability of an organism to tolerate adverse environments, such as dehydration and low temperatures, still represents an unsolved and fascinating problem. It has been shown that many sugars play an important role as bioprotectant agents, and among the best performers is the disaccharide trehalose. The current hypothesis links the efficiency of its protective role to strong modifications of the tetrahedral arrangement of water molecules in the sugar hydration shell, with trehalose forming many hydrogen bonds with the solvent. Here, we show, by means of state-of-the-art neutron diffraction experiments combined with EPSR simulations, that trehalose solvation induces very minor modifications of the water structure. Moreover, the number of water molecules hydrogen-bonded to the sugar is surprisingly small.

Correlated atomic motions in liquid deuterium fluoride studied by coherent quasielastic neutron scattering.

The collective dynamics of liquid deuterium fluoride are studied by means of high-resolution quasielastic and inelastic neutron scattering over a range of four decades in energy transfer. The spectra show a low-energy coherent quasielastic component which arises from correlated stochastic motions as well as a broad inelastic feature originating from overdamped density oscillations. While these results are at variance with previous works which report on the presence of propagating collective modes, they are fully consistent with neutron diffraction, nuclear magnetic resonance, and infrared/Raman experiments on this prototypical hydrogen-bonded fluid.

Observation of fractional Stokes-Einstein behavior in the simplest hydrogen-bonded liquid.

Quasielastic neutron scattering has been used to investigate the single-particle dynamics of hydrogen fluoride across its entire liquid range at ambient pressure. For T>230 K, translational diffusion obeys the celebrated Stokes-Einstein relation, in agreement with nuclear magnetic resonance studies. At lower temperatures, we find significant deviations from the above behavior in the form of a power law with exponent xi=-0.71+/-0.05. More striking than the above is a complete breakdown of the Debye-Stokes-Einstein relation for rotational diffusion. Our findings provide the first experimental verification of fractional Stokes-Einstein behavior in a hydrogen-bonded liquid, in agreement with recent computer simulations [S. R. Becker, Phys. Rev. Lett. 97, 055901 (2006)10.1103/PhysRevLett.97.055901].

The hydration of the neurotransmitter acetylcholine in aqueous solution.

Neutron diffraction augmented with hydrogen isotope substitution has been used to examine the water structure around the acetylcholine molecular ion in aqueous solution. It is shown that the nearest-neighbor water molecules in the region around the trimethylammonium headgroup are located either in a ring around the central nitrogen atom or between the carbon atoms, forming a sheath around the onium group. Moreover the water molecules in this cavity do not bond to the onium group but rather form hydrogen bonds with water molecules in the surrounding aqueous environment. Given that in the bound state the onium headgroup must be completely desolvated, the absence of bonding between the onium headgroup and the surrounding water solvent may be selectively favorable to acetylcholine-binding in the receptor site. Away from the headgroup, pronounced hydrogen-bonding of water to the carbonyl oxygen is observed, but not to the ether oxygen in the acetylcholine chain.

Evidence of the presence of opticlike collective modes in a liquid from neutron scattering experiments.

Inelastic neutron scattering data from liquid DF close to the melting point show, in addition to spectra comprising quasielastic and heavily damped acoustic motions, an intense, nondispersive band centered at about 27 meV along with a broader higher energy feature. Observation of the former band provides the first direct verification of the existence within the liquid state of collective opticlike excitations as predicted by molecular dynamics simulations. The latter corresponds to mainly reorientational motions assigned from mode eigenvector analysis carried out by computer simulations.

On the variation of the structure of liquid deuterium fluoride with temperature.

The structure of liquid deuterium fluoride has been measured using pulsed neutron diffraction and high energy x-ray diffraction techniques as a function of temperature. The neutron experiments were performed at T=296+/-2 K, 246+/-2 K, and 193+/-2 K and the x-ray measurements carried out at 296+/-2 K and 195+/-2 K. The x-ray pair correlation functions, which are dominated by fluorine-fluorine interactions, show the first peak at approximately 2.53+/-0.05 A remains very nearly invariant with decreasing temperature. Peaks around 4.5 and 5.0 A also appear at both temperatures in the x-ray data. In contrast, the intermolecular peaks in the total neutron pair correlation function show that significant systematic local structural changes occur as the temperature is lowered. The first intermolecular peak position shortens from 1.64+/-0.05 A at 296 K to 1.56+/-0.05 A at 195 K. Although there are overlapping contributions from the intermolecular hydrogen-fluorine and hydrogen-hydrogen correlations, it is clear that the temperature dependent structural changes are largely due to a rearrangement of the deuterium atom positions in the fluid. By comparison with partial structure factor data the hydrogen bonds appear to become more linear at lower temperatures.