Mechanistic Insights into Polyphenols' Aggregation Inhibition of α-Synuclein and Related Peptides.

While several polyphenols were found to either inhibit or modulate the aggregation of proteins implicated in neurodegenerative diseases, such as Parkinson's disease (PD), discrepant action mechanisms have been reported. This, in addition to some polyphenols' pan-assay interference compounds' reputation, casts some doubts concerning their therapeutic relevance. Here, we studied, through molecular dynamics and enhanced sampling methods, the aggregation of 11-mer peptides from the non-amyloid-ß component, an aggregation-prone domain of α-synuclein (α-syn) implicated in PD and other synucleinopathies, in neat water and aqueous solutions of resveratrol (RSV) and gallic acid (GA). Further, simulations of the complete protein were carried out in aqueous urea, RSV, and GA solutions. Our results show that peptide aggregation is not disrupted by either phenolic compound. Thus, instead, intrusion of RSV and GA in the inter-peptide region induces a peptide-peptide re-orientation, favoring terminal interactions that manifest in the formation of barrierless solvent-separated configurations. Moreover, although the (poly)phenols induce a pronounced peptide dewetting at high concentrations, ß-sheet-rich regions, a hallmark of α-syn aggregation, are not disrupted. Thus, our results indicate that, if anything, RSV and GA delay or modulate peptide aggregation at high concentrations via the stabilization of solvent-separated conformations as opposed to aggregation inhibition. Structural analysis of the full protein, however, shows that the (poly)phenols induce more extended conformations of α-syn, similar to urea, possibly also influencing its aggregation propensity. However, opposite to urea, the (poly)phenols reduce α-syn's conformational space, likely due to steric effects and a slowdown of the solvent dynamics. These effects are concentration-dependent and possibly unattainable at therapeutic-relevant concentrations. These results suggest that the aggregation inhibition activity of RSV and GA in vitro should involve, instead, either the non-covalent binding to oligomeric intermediates or the stabilization of the monomer and/or oligomers through the formation of covalent bonds of the respective quinones with α-syn. In addition, the enhanced aggregation tendency of the peptides observed here could be associated with the formation of non-toxic oligomers, reported for some polyphenols.

Protein aggregation-inhibition: a therapeutic route from Parkinson's disease to sickle cell anemia.

Protein aggregation is implicated in multiple diseases, so-called proteinopathies, ranging from neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease (PD) to type 2 diabetes mellitus and sickle cell disease (SCD). The structure of the protein aggregates and the kinetics and mechanisms of aggregation have been the object of intense research over the years toward the development of therapeutic routes, including the design of aggregation inhibitors. Nonetheless, the rational design of drugs targeting aggregation inhibition remains a challenging endeavor because of multiple, disease-specific factors, including an incomplete understanding of protein function, the multitude of toxic and non-toxic protein aggregates, the lack of specific drug binding targets, discrepant action mechanisms of aggregation inhibitors, or a low selectivity, specificity, and/or drug potency, reflected in the high concentrations required for some inhibitors to be effective. Herein, we provide a perspective of this therapeutic route with emphasis on small molecules and peptide-based drugs in two diverse diseases, PD and SCD, aiming at establishing links among proposed aggregation inhibitors. The small and large length-scale regimes of the hydrophobic effect are discussed in light of the importance of hydrophobic interactions in proteinopathies. Some simulation results are reported on model peptides, illustrating the impact of hydrophobic and hydrophilic groups in water's hydrogen-bond network with an impact on drug binding. The seeming importance of aromatic rings and hydroxyl groups in protein-aggregation-inhibitor-drugs is emphasized along with the challenges associated with some inhibitors, limiting their development into effective therapeutic options, and questioning the potential of this therapeutic route.

Aggregation of a Parkinson's Disease-Related Peptide: When Does Urea Weaken Hydrophobic Interactions?

While the exact cause of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease is not completely understood, compelling evidence implicates the aggregation of specific proteins and peptides. Co-solvents can provide molecular insight into protein aggregation mechanisms and the chemical nature of potential aggregation inhibitors. Here, we study, through molecular simulations, the hydration and binding free energies of an amphiphilic peptide from the nonamyloid-ß component (NAC), a key aggregation-prone domain of α-synuclein, in water and an 8 M aqueous urea solution. Isoleucine, glycine, and serine peptides of the same length are also studied to unravel the role of urea in the hydration and aggregation of hydrophobic and hydrophilic domains. A strong impact of urea in hindering the aggregation of the NAC subdomain is observed. A slightly weaker aggregation inhibition is observed for the Gly and Ser peptides, whereas a much lower aggregation inhibitory activity is found for the Ile peptide, seemingly contrasting with urea's protein unfolding mechanism. This behavior is shown to derive from a lower profusion of urea next to the hydrophobic side chains and the backbone of the Ile's peptide in the dimeric form. As a consequence, ß-sheets, formed upon aggregation, remain nearly intact. Hydrophilic neighbor groups in the amphiphilic NAC subdomain, however, are shown to anchor enough urea to weaken hydrophobic interactions and disrupt ß-sheet structures. Our results indicate that urea's activity is potentiated in amphiphilic domains and that potential drugs could disrupt hydrophobic ß-sheet-rich regions while not binding primarily to hydrophobic amino acids.

Effect of urea on the hydration and aggregation of hydrophobic and amphiphilic solute models: Implications to protein aggregation.

Despite the emergence of a molecular picture of urea's protein unfolding mechanism in the past few decades, less is known about its action mechanism on protein aggregation. This is especially relevant for understanding the aggregation of amyloid proteins and peptides, implicated in several neurodegenerative diseases. While urea is believed to weaken the hydrophobic effect, a picture consistent with the decrease in the excess chemical potential of sufficiently large alkanes, interactions with protein polar side chains and backbone atoms are also important. Here, we study, through molecular dynamics, the hydration and aggregation of several alkanes and amphiphilic "mutants" of n-dodecane, in an 8M aqueous urea solution, aiming at getting insight into urea's mode of action. A size-dependent crossover temperature is found, above which the hydration of the alkanes is favored in the aqueous urea solution. The hydration of the alkanes is enhanced via entropy, with the enthalpy opposing hydration, consistent with experiments. The reason is that although solute-solvent interactions are favorable, these are overwhelmed by urea-water and urea-urea interactions. In contrast, water-water interactions and entropy are favored by a water depletion around the solute and a reduced water depletion around methane explains its exceptional solubility decrease. Furthermore, we show that while urea favors the hydration of n-dodecane and the amphiphilic mutants, it slightly enhances and reduces, respectively, the aggregation of the alkanes and the amphiphilic mutants. Thus, opposite to the common view, our results show that urea does not necessarily weaken hydrophobic interactions despite solvation being favored.

On the Nonaggregation of Normal Adult Hemoglobin and the Aggregation of Sickle Cell Hemoglobin.

Sickle cell disease is a genetic disorder associated with a single mutation (Glu-ß6 → Val-ß6) in the ß chains of hemoglobin, causing the polymerization of deoxygenated sickle cell hemoglobin (deoxy-HbS). The deoxy-HbS binding free energy was recently studied through molecular simulations, and a value of -14 ± 1 kcal mol-1 was found. Here, we studied the binding free energy of normal adult hemoglobin (deoxy-HbA), which does not polymerize at normal physiological conditions, with the aim of elucidating the importance of the presence of Val-ß6 and of the absence of Glu-ß6 on the aggregation of deoxy-HbS. A binding free energy of -4.4 ± 0.5 kcal mol-1 was found from a one-dimensional potential of mean force. Hydrophobic interactions are shown to represent less than 20% of the interactions in the contact interface, and despite similarly strong hydrogen-bonded ion pairs (i.e., salt bridges) and water bridged electrostatic interactions are found for deoxy-HbA and deoxy-HbS, a large repulsive potential energy is associated with Glu-ß6, whereas a mild attractive potential energy is connected with Val-ß6. Interestingly, Asp-ß73 switches from forming a major electrostatic repulsive pair with Glu-ß6 in deoxy-HbA, to forming a major attractive residue pair with Val-ß6 in deoxy-HbS, consistent with the view that damping of electrostatic repulsions involving Glu-ß6, namely, those associated with Asp-ß73, could be responsible for the polymerization of deoxy-HbA at high potassium phosphate concentrations. Solvation analysis shows that functional groups forming salt bridges and water bridged interactions preserve a nearly intact first hydration sphere, avoiding a complete dewetting free energy penalty. These results support the view that the absence of Glu-ß6 is more important than the presence of Val-ß6, and that although hydrophobic effects, associated with the Val-ß6 dehydration and interaction with the hydrophobic pocket in the neighbor tetramer, are important, electrostatic interactions are dominant, opposite to a picture where HbS association is driven by hydrophobic interactions.

On the Binding Free Energy and Molecular Origin of Sickle Cell Hemoglobin Aggregation.

Protein aggregation is associated with various diseases, including Alzheimer and Parkinson as well as sickle cell disease (SCD). From a molecular point of view, protein aggregation depends on a complex balance of electrostatic and hydrophobic interactions mediated by water. An impressive manifestation of the importance of this balance concerns the human hemoglobin (HbA) mutant, HbS (sickle cell Hb), where a single substitution at the 6th position of HbA ß-chains, from glutamic acid to valine, causes the polymerization of deoxygenated HbS (deoxy-HbS), responsible for SCD. HbS polymerization is believed to occur via a double nucleation mechanism initiated by the formation of HbS fibers (homogeneous nucleation), followed by fiber growth. Furthermore, it was proposed that homogeneous nucleation proceeds through a two-step mechanism, where metastable dense clusters play the role of nucleation precursors. Thus, hindering or delaying the formation of such precursors could represent a potential SCD therapeutic route. Here, we study, through molecular dynamics, the binding free energy and protein-protein contacts involved in the deoxy-HbS dimer aggregation and stabilization process. A binding free energy of ∼-14.0 ± 1 kcal/mol is estimated from a one-dimensional potential of mean force. Analysis of protein-protein interactions shows that both electrostatic and van der Waals interactions play an important role on the aggregation of HbS. With respect to the former, our results indicate that aggregation is largely favored by the formation of salt bridges (SB), mostly, Lys-Glu, Lys-Asp, and Heme-Lys SB, which outweigh electrostatic repulsions involving similar residues. Thus, our results suggest that a potential antisickling drug could be one with the ability to weaken or hinder the formation of a few SB between carboxylate and ammonium groups.

Magnetic properties and core electron binding energies of liquid water.

The magnetic properties and the core and inner valence electron binding energies of liquid water are investigated. The adopted methodology relies on the combination of molecular dynamics and electronic structure calculations. Born-Oppenheimer molecular dynamics with the Becke and Lee-Yang-Parr functionals for exchange and correlation, respectively, and includes an empirical correction (BLYP-D3) functional and classical molecular dynamics with the TIP4P/2005-F model were carried out. The Keal-Tozer functional was applied for predicting magnetic shielding and spin-spin coupling constants. Core and inner valence electron binding energies in liquid water were calculated with symmetry adapted cluster-configuration interaction. The relationship between the magnetic shielding constant σ(17O), the role played by the oxygen atom as a proton acceptor and donor, and the tetrahedral organisation of liquid water are investigated. The results indicate that the deshielding of the oxygen atom in water is very dependent on the order parameter (q) describing the tetrahedral organisation of the hydrogen bond network. The strong sensitivity of magnetic properties on changes of the electronic density in the nuclei environment is illustrated by a correlation between σ(17O) and the energy gap between the 1a1[O1s] (core) and the 2a1 (inner valence) orbitals of water. Although several studies discussed the eventual connection between magnetic properties and core electron binding energies, such a correlation could not be clearly established. Here, we demonstrate that for liquid water this correlation exists although involving the gap between electron binding energies of core and inner valence orbitals.

On the hydrogen-bond network and the non-Arrhenius transport properties of water.

We study the structural and dynamic transformations of SPC/E water with temperature, through molecular dynamics (MD), and discuss the non-Arrhenius behavior of the transport properties and orientational dynamics, and the magnitude of the breakdown of the Stokes-Einstein (SE) and the Stokes-Einstein-Debye (SED) relations, in the light of these transformations. Our results show that deviations from Arrhenius behavior of the self-diffusion at low temperatures cannot be exclusively explained by the reduction of water defects (interstitial waters) and the increase of the local tetrahedrality, thus, suggesting the importance of the slowdown of collective rearrangements. Interestingly we find that at high temperatures (T ⩾ 340 K) water defects lead to a slight increase of the tetrahedrality and a decrease of the self-diffusion, opposite to water at low temperatures. The relative magnitude of the breakdown of the SE and the SED relations is found to be in accord with recent experiments (Dehaoui et al 2015 Proc. Natl Acad. Sci. USA 112 12020) resolving the discrepancy with previous MD results. Further, we show that SPC/E hydrogen-bond (HB) lifetimes deviate from Arrhenious behaviour at low temperatures in contrast with some previous MD studies. This deviation is nevertheless much smaller than that observed for the orientational dynamics and the transport properties of water, consistent with the relaxation times measured by several experimental methods. The HB acceptor exchange dynamics defined here by the acceptor switch and reform (librational dynamics) frequencies exhibit similar Arrhenius deviations, thus explaining to some extent the non-Arrhenius behavior of the transport properties and of the orientational dynamics of water. Our results also show that the fraction of HB switches through a bifurcated pathway follow a power law with the temperature decrease. Thus, at low temperatures HB acceptor switches are less frequent but occur on a faster time scale consistent with the temperature dependence of the ratio of the rotational relaxation times for the different Legendre polynomial ranks.

Fast and slow dynamics and the local structure of liquid and supercooled water next to a hydrophobic amino acid.

We study, through molecular dynamics simulations, the structure and orientational dynamics of water next to a blocked hydrophobic amino acid, valine (Val), above and below the freezing point of water. The structure and the orientational dynamics of waters with four water neighbors (4WN) and less than four water neighbors (L4WN) in the Val's coordination sphere are deconvoluted. We find that in spite of the excluded volume effects waters with L4WN have faster librational dynamics than bulk water, reminiscent of water at the liquid-vapor interface, and faster orientational dynamics than waters with 4WN, at every temperature. Furthermore, our results show that the pronounced decrease of the orientational retardation factor below ∼255 K observed experimentally is mostly caused by the acceleration of the orientational dynamics of waters with L4WN, while waters with 4WN exhibit only moderate acceleration. The differences between the hydrogen-bond acceptor switching mechanism in the shell and the bulk are also analyzed, and no evidence of especially slow OH groups neither in the 4WN nor in the L4WN populations is found. Finally, we show that waters with 4WN have higher tetrahedrality than bulk water at every temperature although this difference decreases at both high and low temperatures.

Water tetrahedrons, hydrogen-bond dynamics, and the orientational mobility of water around hydrophobic solutes.

Despite being intensively studied, the magnitude of specific structural and dynamic perturbations of water next to hydrophobic surfaces remains a matter of debate. Here we show, from molecular dynamics, that the structure of a subset of water molecules in the first hydration layer, those preserving four nearest water neighbors, resembles that of water at ∼10 °C, and that the origin of the orientational slowdown is mainly a decrease of the hydrogen-bond (HB) acceptor switch frequency, while water structuring plays a minor role, slightly accelerating HB acceptor switches. By portraying the mean HB dynamics of water as a doubly periodic event, we demonstrate that the orientational retardation factor is effectively defined by the ratio of the HB acceptor switch period in the hydration layer and bulk. Excluded volume delays HB acceptor switches, accelerating the orientational relaxation of ∼1/3 of the water molecules on the hydration layer in this time scale, but this is largely exceeded by the decrease of the HB switch frequency, consistent with 2D IR spectroscopy experiments, and at the origin of longer HB lifetimes. The orientational mobility of water populations with long HB lifetimes is also probed, and although a relaxation plateau is observed at ∼10 ps consistent with fs IR spectroscopy experiments, no water molecule is rotationally frozen at any time scale. The proposed molecular picture is consistent with fs IR, 2D IR, and NMR experimental results on the orientational retardation of water and reveals the magnitude of "hidden" enhanced ordered water pentamers formed near hydrophobic solutes.

Insights on hydrogen-bond lifetimes in liquid and supercooled water.

We study the temperature dependence of the lifetime of geometric and geometric/energetic water hydrogen-bonds (H-bonds), down to supercooled water, through molecular dynamics. The probability and lifetime of H-bonds that break either by translational or librational motions and those of energetic broken H-bonds, along with the effects of transient broken H-bonds and transient H-bonds, are considered. We show that the fraction of transiently broken energetic H-bonds increases at low temperatures and that this energetic breakdown is caused by oxygen-oxygen electrostatic repulsions upon too small amplitude librations to disrupt geometric H-bonds. Hence, differences between geometric and energetic continuous H-bond lifetimes are associated with large H-bond energy fluctuations, in opposition to moderate geometric fluctuations, within common energetic and geometric H-bond definition thresholds. Exclusion of transient broken H-bonds and transient H-bonds leads to H-bond definition-independent mean lifetimes and activation energies, ~11 kJ/mol, consistent with the reactive flux method and experimental scattering results. Further, we show that power law decay of specific temporal H-bond lifetime probability distributions is associated with librational and translational motions that occur on the time scale (~0.1 ps) of H-bond breaking /re-forming dynamics. While our analysis is diffusion-free, the effect of diffusion on H-bond probability distributions where H-bonds are allowed to break and re-form, switching acceptors in between, is shown to result in neither exponential nor power law decay, similar to the reactive flux correlation function.

Water's structure around hydrophobic solutes and the iceberg model.

The structure of water in the hydration shells of small hydrophobic solutes was investigated through molecular dynamics. The results show that a subset of water molecules in the first hydration shell of a nonpolar solute have a significantly enhanced tetrahedrality and a slightly larger number of hydrogen bonds, relative to the molecules in water at room temperature, consistent with the experimentally observed negative excess entropy and increased heat capacity of hydrophobic solutions at room temperature. This ordering results from the rearrangement of a small number of water molecules near the nonpolar solutes that occupy one to two vertices of the enhanced water tetrahedra. Although this structuring is not nearly like that often associated with a literal interpretation of the term "iceberg" in the Frank and Evans iceberg model, it does support a moderate interpretation of this model. Thus, the tetrahedral orientational order of this ensemble of water molecules is comparable to that of liquid water at ~10 °C, although not accompanied by the small contraction of the O-O distance observed in cold water. Further, we show that the structural changes of water in the vicinity of small nonpolar solutes cannot be inferred from the water radial distribution functions, explaining why this increased ordering is not observed through neutron diffraction experiments. The present results restore a molecular view where the slower translational and reorientational dynamics of water near hydrophobic groups has a structural equivalent resembling water at low temperatures.

On the effects of temperature, pressure, and dissolved salts on the hydrogen-bond network of water.

We study the structure of water through molecular dynamics, specifically the compression/expansion of the hydrogen-bond (H-bond) network, with temperature and pressure, and in salt solutions of alkali chlorides and sodium halides, and relate the observed local spatial perturbations with the tetrahedrality and the average number and lifetime of water H-bonds. The effect of transient H-bonds and transient broken H-bonds on H-bond lifetimes is further investigated, and results are compared with depolarized Rayleigh scattering lifetimes for neat water. A significant electrostriction is observed in the first hydration shell of Li(+) and F(-), while larger ions cause a small expansion of the H-bond network of water instead. However, both alkali cations and halide anions induce a minor contraction of the H-bond network in the second hydration shell. Further, water in the second hydration shell of Li(+), Na(+), and K(+) is less tetrahedral than neat water, resembling water at high pressures, while the H-bond network in the respective hydration shell of halide anions resembles water at low temperatures. Nevertheless, neither ion induced H-bond contraction nor expansion can be exactly mapped onto P or T effects on the local structure of water. Even though the average number and lifetime of H-bonds in the ionic hydration shells of most ions are not very different from those found in neat water, Li(+) and F(-) significantly increase the lifetime of water donor and acceptor H-bonds, respectively, in the first hydration shell. The non-monotonic increase of cation and anion mobility, with ionic size, observed experimentally, is interpreted in terms of the water local tetrahedrality around cations and anions.

Mapping structural perturbations of water in ionic solutions.

The structure of water in sodium halide aqueous solutions at different concentrations is studied through molecular dynamics. Emphasis is placed on the extent of ionic-induced changes in the water structure, and the concept of kosmotropes/chaotropes is probed, in terms of perturbations to the tetrahedral H-bond network of water. The results show that at low salt concentrations, the halide anions slightly increase the tetrahedrality of the H-bond network of water in the anionic second hydration shell and I(-) is found to be the strongest kosmotrope, contrary to its structure breaker reputation. The sodium cation in turn induces a significant loss of tetrahedrality in the second cationic hydration shell. At higher concentrations, the dominant disruptive effect of Na(+) cancels the anionic effects, even in the anionic second hydration shell. According to a kosmotropes/chaotropes classification of ions, based on the tetrahedrality of the H-bond network of water, halide anions are therefore weak kosmotropes, while Na(+) is a strong chaotrope. However, if this classification is applied to the salts, rather than to the ions, all of the sodium halides are classified as structure breakers even at low concentrations. Further, the effect of pressure on the tetrahedrality of the H-bond network of water is found to be similar to the average effect of the dissolved salts. The present results indicate that the classification of ions in kosmotropes/chaotropes in terms of long-range perturbations to the tetrahedral H-bond network of water is not correlated to the position of the ions in the respective Hofmeister series.

Electronic properties of hydrogen-bonded complexes of benzene(HCN)(1-4): comparison with benzene(H2O)(1-4).

The electronic properties, specifically, the dipole and quadrupole moments and the ionization energies of benzene (Bz) and hydrogen cyanide (HCN), and the respective binding energies, of complexes of Bz(HCN)(1-4), have been studied through MP2 and OVGF calculations. The results are compared with the properties of benzene-water complexes, Bz(H(2)O)(1-4), with the purpose of analyzing the electronic properties of microsolvated benzene, with respect to the strength of the CH/π and OH/π hydrogen-bond (H-bond) interactions. The linear HCN chains have the singular ability to interact with the aromatic ring, preserving the symmetry of the latter. A blue shift of the first vertical ionization energies (IEs) of benzene is observed for the linear Bz(HCN)(1-4) clusters, which increases with the length of the chain. NBO analysis indicates that the increase of the IE with the number of HCN molecules is related to a strengthening of the CH/π H-bond, driven by cooperative effects, increasing the acidity of the hydrogen cyanide H atom involved in the π H-bond. The longer HCN chains (n ≥ 3), however, can bend to form CH/N H-bonds with the Bz H atoms. These cyclic structures are found to be slightly more stable than their linear counterparts. For the nonlinear Bz(HCN)(3-4) and Bz(H(2)O)(2-4) complexes, an increase of the binding energy with the number of solvent molecules and a decrease of the IE of benzene, relative to the values for the Bz(HCN) and Bz(H(2)O) complexes, respectively, are observed. Although a strengthening of the CH/π and OH/π H-bonds, with increasing n, also takes place for the Bz(H(2)O)(2-4) and Bz(HCN)(3-4) nonlinear complexes, Bz proton donor, CH/O, and CH/N interactions are at the origin of this decrease. Thus CH/π and OH/π H-bonds lead to higher IEs of Bz, whereas the weaker CH/N and CH/O H-bond interactions have the opposite effect. The present results emphasize the importance of both aromatic XH/π (X = C, O) and CH/X (X = N, O) interactions for understanding the structure and electronic properties of Bz(HCN)(n) and Bz(H(2)O)(n) complexes.

Molecular dynamics study of the vaporization of an ionic drop.

The melting of a microcrystal in vacuum and subsequent vaporization of a drop of NaCl were studied through molecular dynamics simulations with the Born-Mayer-Huggins-Tosi-Fumi rigid-ion effective potential. The vaporization was studied for a single isochor at increasing temperatures until the drop completely vaporized, and gaseous NaCl formed. Examination of the vapor composition shows that the vapor of the ionic drop and gaseous NaCl are composed of neutral species, the most abundant of which, ranging from simple NaCl monomers (ion pairs) to nonlinear polymers, (Na(n)Cl(n))(n=2-4). The enthalpies of sublimation, vaporization, and dissociation of the different vapor species are found to be in reasonable agreement with available experimental data. The decrease of the enthalpy of vaporization of the vapor species, with the radius of the drop decrease, accounts for a larger fraction of trimers and tetramers than that inferred from experiments. Further, the rhombic dimer is significantly more abundant than its linear isomer although the latter increases with the temperature. The present results suggest that both trimers and linear dimers may be important to explain the vapor pressure of molten NaCl at temperatures above 1500 K.

Born-Oppenheimer molecular dynamics of the hydration of Na+ in a water cluster.

The hydration of Na(+) in a water cluster is studied through all-electron Born-Oppenheimer molecular dynamics. The structure, dipole moment, and vibrational spectrum of the sodium cation hydration shells are examined. Emphasis is placed on the extent of the effect of the hydrated cation on the cluster properties. Our results show that hydration of Na(+) takes place in the interior of the cluster leading to significant changes in the hydrogen-bond (H-bond) network beyond the first hydration shell. In particular, we find that single acceptor-only H-bond arrangements increase significantly at the surface of the cluster relative to a neat water cluster. The vibrational spectrum of the first hydration shell of the cation, comprised mostly of H-bond double donor-single acceptor water molecules, is similar to that found for water molecules in the interior of a neat water cluster, although a small blue shift of the OH stretching band is observed. Further, a small reduction of the dipole moment of water molecules in the first hydration shell of the cation relative to a neat water cluster is also observed, and this persists to a minor extent when we move from the interior to the surface of the cluster. The present results indicate that the effect of the Na(+) on the cluster properties, although not pronounced, is not constrained to the first hydration shell. The reason appears to lie mostly in the specific orientation of the water molecules in the first coordination sphere, inducing modifications on the H-bond network topology of the cluster.

The changing hydrogen-bond network of water from the bulk to the surface of a cluster: a born-oppenheimer molecular dynamics study.

The effect of the environment on the properties of water in the bulk and at the surface of a cluster is studied by all-electron Born-Oppenheimer molecular dynamics. The vibrational spectrum of surface and bulk water is interpreted in terms of the molecular orientation and the local changes in the H-bond network of the cluster. Our results show that, in spite of the presence of a surface moiety of "acceptor-only" molecules, the H-bond network is significantly more labile at the surface than in the bulk part of cluster, and single donor-acceptor arrangements are largely dominant at the interface. Further, although surface water molecules depict in average a single H atom protruding into the vapor, molecules exhibit significant orientational freedom. These results explain the apparently opposite experimental observations from infrared sum frequency generation and X-ray spectroscopy of the liquid-vapor interface. The dipole moment, intramolecular geometry and surface relaxation are also analyzed at light of the different H-bond regions in the cluster.

First principles molecular dynamics of molten NaI: structure, self-diffusion, polarization effects, and charge transfer.

The structure and self-diffusion of NaI and NaCl at temperatures close to their melting points are studied by first principles Hellmann-Feynman molecular dynamics (HFMD). The results are compared with classical MD using rigid-ion (RI) and shell-model (ShM) interionic potentials. HFMD for NaCl was reported before at a higher temperature [N. Galamba and B. J. Costa Cabral, J. Chem. Phys. 126, 124502 (2007)]. The main differences between the structures predicted by HFMD and RI MD for NaI concern the cation-cation and the anion-cation pair correlation functions. A ShM which allows only for the polarization of I- reproduces the main features of the HFMD structure of NaI. The inclusion of polarization effects for both ionic species leads to a more structured ionic liquid, although a good agreement with HFMD is also observed. HFMD Green-Kubo self-diffusion coefficients are larger than those obtained from RI and ShM simulations. A qualitative study of charge transfer in molten NaI and NaCl was also carried out with the Hirshfeld charge partitioning method. Charge transfer in molten NaI is comparable to that in NaCl, and results for NaCl at two temperatures support the view that the magnitude of charge transfer is weakly state dependent for ionic systems. Finally, Hirshfeld charge distributions indicate that differences between RI and HFMD results are mainly related to polarization effects, while the influence of charge transfer fluctuations is minimal for these systems.