Voltage-sensing domains (VSDs) sense changes in the membrane electrostatic potential and, through conformational changes, regulate a specific function. The VSDs of wild-type voltage-dependent K+, Na+, and Ca2+ channels do not conduct ions, but they can become ion-permeable through pathological mutations in the VSD. Relatively little is known about the underlying mechanisms of conduction through VSDs. The most detailed studies have been performed on Shaker K+ channel variants in which ion conduction through the VSD is manifested in electrophysiology experiments as a voltage-dependent inward current, the so-called omega current, which appears when the VSDs are in their resting state conformation. Only monovalent cations appear to permeate the Shaker VSD via a pathway that is believed to be, at least in part, the same as that followed by the S4 basic side chains during voltage-dependent activation. We performed μs-time scale atomistic molecular dynamics simulations of a cation-conducting variant of the Shaker VSD under applied electric fields in an experimentally validated resting-state conformation, embedded in a lipid bilayer surrounded by solutions containing guanidinium chloride or potassium chloride. Our simulations provide insights into the Shaker VSD permeation pathway, the protein-ion interactions that control permeation kinetics, and the mechanism of voltage-dependent activation of voltage-gated ion channels.

It is now well established by numerous experimental and computational studies that the adsorption propensities of inorganic anions conform to the Hofmeister series. The adsorption propensities of inorganic cations, such as the alkali metal cations, have received relatively little attention. Here we use a combination of liquid-jet X-ray photoelectron experiments and molecular dynamics simulations to investigate the behavior of K+ and Li+ ions near the interfaces of their aqueous solutions with halide ions. Both the experiments and the simulations show that Li+ adsorbs to the aqueous solution−vapor interface, while K+ does not. Thus, we provide experimental validation of the “surfactant-like” behavior of Li+ predicted by previous simulation studies. Furthermore, we use our simulations to trace the difference in the adsorption of K+ and Li+ ions to a difference in the resilience of their hydration shells.

It is now well established by numerous experimental and computational studies that the adsorption propensities of inorganic anions conform to the Hofmeister series. The adsorption propensities of inorganic cations, such as the alkali metal cations, have received relatively little attention. Here we use a combination of liquid-jet X-ray photoelectron experiments and molecular dynamics simulations to investigate the behavior of K+ and Li+ ions near the interfaces of their aqueous solutions with halide ions. Both the experiments and the simulations show that Li+ adsorbs to the aqueous solution−vapor interface, while K+ does not. Thus, we provide experimental validation of the “surfactant-like” behavior of Li+ predicted by previous simulation studies. Furthermore, we use our simulations to trace the difference in the adsorption of K+ and Li+ ions to a difference in the resilience of their hydration shells.

It is now well established by numerous experimental and computational studies that the adsorption propensities of inorganic anions conform to the Hofmeister series. The adsorption propensities of inorganic cations, such as the alkali metal cations, have received relatively little attention. Here we use a combination of liquid-jet X-ray photoelectron experiments and molecular dynamics simulations to investigate the behavior of K+ and Li+ ions near the interfaces of their aqueous solutions with halide ions. Both the experiments and the simulations show that Li+ adsorbs to the aqueous solution−vapor interface, while K+ does not. Thus, we provide experimental validation of the “surfactant-like” behavior of Li+ predicted by previous simulation studies. Furthermore, we use our simulations to trace the difference in the adsorption of K+ and Li+ ions to a difference in the resilience of their hydration shells.

It is now well established by numerous experimental and computational studies that the adsorption propensities of inorganic anions conform to the Hofmeister series. The adsorption propensities of inorganic cations, such as the alkali metal cations, have received relatively little attention. Here we use a combination of liquid-jet X-ray photoelectron experiments and molecular dynamics simulations to investigate the behavior of K+ and Li+ ions near the interfaces of their aqueous solutions with halide ions. Both the experiments and the simulations show that Li+ adsorbs to the aqueous solution−vapor interface, while K+ does not. Thus, we provide experimental validation of the “surfactant-like” behavior of Li+ predicted by previous simulation studies. Furthermore, we use our simulations to trace the difference in the adsorption of K+ and Li+ ions to a difference in the resilience of their hydration shells.

We report molecular dynamics simulations of acetonitrile–water binary solutions at concentrations of 0.032–0.59 mole fraction. We find that at low bulk concentration acetonitrile has an enhanced population near the liquid/vapor interface. The surface-bound acetonitrile molecules exhibit anisotropic orientations and lie nearly flat along the solution surface with their terminal methyl groups directed toward the vapor. Upon increasing the bulk concentration, the formation of acetonitrile domains is promoted by interactions between hydrophobic methyl moieties. Dipole–dipole interactions facilitate a pseudonematic, antiparallel pairing of near-neighbor molecules both in the bulk solution and near the liquid/vapor interface. Near the interface the preferred orientation of acetonitrile flattens further to accommodate antiparallel pairing of neighboring molecules such that the methyl group remains above the solution. This study paints a surprisingly complex picture of a binary organic–water solution that manifests behavior similar to liquid crystals through preferred orientations and pseudonematic antiparallel pairing.

We present a novel multi-conformation Monte Carlo simulation method that enables the modeling of protein–protein interactions and aggregation in crowded protein solutions. This approach is relevant to a molecular-scale description of realistic biological environments, including the cytoplasm and the extracellular matrix, which are characterized by high concentrations of biomolecular solutes (e.g., 300–400 mg/mL for proteins and nucleic acids in the cytoplasm of Escherichia coli). Simulation of such environments necessitates the inclusion of a large number of protein molecules. Therefore, computationally inexpensive methods, such as rigid-body Brownian dynamics (BD) or Monte Carlo simulations, can be particularly useful. However, as we demonstrate herein, the rigid-body representation typically employed in simulations of many-protein systems gives rise to certain artifacts in protein–protein interactions. Our approach allows us to incorporate molecular flexibility in Monte Carlo simulations at low computational cost, thereby eliminating ambiguities arising from structure selection in rigid-body simulations. We benchmark and validate the methodology using simulations of hen egg white lysozyme in solution, a well-studied system for which extensive experimental data, including osmotic second virial coefficients, small-angle scattering structure factors, and multiple structures determined by X-ray and neutron crystallography and solution NMR, as well as rigid-body BD simulation results, are available for comparison.

Leishmania major, the parasitic causative agent of leishmaniasis, produces a heme peroxidase (LmP), which catalyzes the peroxidation of mitochondrial cytochrome c (LmCytc) for protection from reactive oxygen species produced by the host. The association of LmP and LmCytc, which is known from kinetics measurements to be very fast (∼108 M–1 s–1), does not involve major conformational changes and has been suggested to be dominated by electrostatic interactions. We used Brownian dynamics simulations to investigate the mechanism of formation of the LmP–LmCytc complex. Our simulations confirm the importance of electrostatic interactions involving the negatively charged D211 residue at the LmP active site, and reveal a previously unrecognized role in complex formation for negatively charged residues in helix A of LmP. The crystal structure of the D211N mutant of LmP reported herein is essentially identical to that of wild-type LmP, reinforcing the notion that it is the loss of charge at the active site, and not a change in structure, that reduces the association rate of the D211N variant of LmP. The Brownian dynamics simulations further show that complex formation occurs via a “bind and crawl” mechanism, in which LmCytc first docks to a location on helix A that is far from the active site, forming an initial encounter complex, and then moves along helix A to the active site. An atomistic molecular dynamics simulation confirms the helix A binding site, and steady state activity assays and stopped-flow kinetics measurements confirm the role of helix A charges in the association mechanism.

The tau protein, whose aggregates are involved in Alzheimer’s disease, is an intrinsically disordered protein (IDP) that regulates microtubule activity in neurons. An IDP lacks a single, well-defined structure and, rather, constantly exchanges among multiple conformations. In order to study IDP dynamics, the combination of experimental techniques, such as neutron scattering, and computational techniques, such as molecular dynamics (MD) simulations, is a powerful approach. Amorphous hydrated powder samples have been very useful for studying protein internal dynamics experimentally, e.g., using neutron scattering. Thus, there is demand for realistic in silico models of hydrated protein powders. Here we present an MD simulation analysis of a powder hydrated at 0.4 g water/g protein of the IDP tau in the temperature range 20–300 K. By comparing with neutron scattering data, we identify the protein–water interface as the predominant feature determining IDP dynamics. The so-called protein dynamical transition is shown to be attenuated, but not suppressed, in the parts of the protein that are not exposed to the solvent. In addition, we find similarities in the mean-squared displacements of the core of a globular protein and “dry” clusters formed by the IDP in hydrated powders. Thus, the ps to ns dynamics of proteins in hydrated powders originate mainly from those residues in contact with solvent. We propose that by measuring the dynamics of protein assemblies, such as aggregates, one might assess qualitatively their state of hydration.

The paired helical filaments (PHF) formed by the intrinsically disordered human protein tau are one of the pathological hallmarks of Alzheimer disease. PHF are fibers of amyloid nature that are composed of a rigid core and an unstructured fuzzy coat. The mechanisms of fiber formation, in particular the role that hydration water might play, remain poorly understood. We combined protein deuteration, neutron scattering, and all-atom molecular dynamics simulations to study the dynamics of hydration water at the surface of fibers formed by the full-length human protein htau40. In comparison with monomeric tau, hydration water on the surface of tau fibers is more mobile, as evidenced by an increased fraction of translationally diffusing water molecules, a higher diffusion coefficient, and increased mean-squared displacements in neutron scattering experiments. Fibers formed by the hexapeptide 306VQIVYK311 were taken as a model for the tau fiber core and studied by molecular dynamics simulations, revealing that hydration water dynamics around the core domain is significantly reduced after fiber formation. Thus, an increase in water dynamics around the fuzzy coat is proposed to be at the origin of the experimentally observed increase in hydration water dynamics around the entire tau fiber. The observed increase in hydration water dynamics is suggested to promote fiber formation through entropic effects. Detection of the enhanced hydration water mobility around tau fibers is conjectured to potentially contribute to the early diagnosis of Alzheimer patients by diffusion MRI.

The major removal processes for gaseous nitric acid (HNO3) in the atmosphere are dry and wet deposition onto various surfaces. The surface in the boundary layer is often covered with organic films, but the interaction of gaseous HNO3 with them is not well understood. To better understand the factors controlling the uptake of gaseous nitric acid and its dissociation in organic films, studies were carried out using single component and mixtures of C8 and C18 alkyl self-assembled monolayers (SAMs) attached to a germanium (Ge) attenuated total reflectance (ATR) crystal upon which a thin layer of SiOx had been deposited. For comparison, diffuse reflectance infrared Fourier transform spectrometry (DRIFTS) studies were also carried out using a C18 SAM attached to the native oxide layer on the surface of silicon powder. These studies show that the alkyl chain length and order/disorder of the SAMs does not significantly affect the uptake or dissociation/recombination of molecular HNO3. Thus, independent of the nature of the SAM, molecular HNO3 is observed up to 70–90% relative humidity. After dissociation, molecular HNO3 is regenerated on all SAM surfaces when water is removed. Results of molecular dynamics simulations are consistent with experiments and show that defects and pores on the surfaces control the uptake, dissociation and recombination of molecular HNO3. Organic films on surfaces in the boundary layer will certainly be more irregular and less ordered than SAMs studied here, therefore undissociated HNO3 may be present on surfaces in the boundary layer to a greater extent than previously thought. The combination of this observation with the results of recent studies showing enhanced photolysis of nitric acid on surfaces suggests that renoxification of deposited nitric acid may need to be taken into account in atmospheric models.

Nitric acid in air is formed by atmospheric reactions of oxides of nitrogen and is removed primarily through deposition to surfaces, either as the gas or after conversion to particulate nitrate. Many of the surfaces and particles have organic coatings, but relatively little is known about the interaction of nitric acid with organic films. We report here studies of the interaction of gaseous HNO3 with a self-assembled monolayer (SAM) formed by reacting 7-octenyltrichlorosilane [H2CCH(CH2)6SiCl3] with the surface of a germanium infrared-transmitting attenuated total reflectance (ATR) crystal that was coated with a thin layer of silicon oxide (SiOx). The SAM was exposed at 298 ± 2 K to dry HNO3 in a flow of N2, followed by HNO3 in humid N2 at a controlled relative humidity (RH) between 20–90%. For comparison, similar studies were carried out using a similar crystal without the SAM coating. Changes in the surface were followed using Fourier transform infared spectroscopy (FTIR). In the case of the SAM-coated crystal, molecular HNO3 and smaller amounts of NO3− ions were observed on the surface upon exposure to dry HNO3. Addition of water vapor led to less molecular HNO3 and more H3O+ and NO3− complexed to water, but surprisingly, molecular HNO3 was still evident in the spectra up to 70% RH. This suggests that part of the HNO3 observed was initially trapped in pockets within the SAM and shielded from water vapor. After increasing the RH to 90% and then exposing the film to a flow of dry N2, molecular nitric acid was regenerated, as expected from recombination of protons and nitrate ions as water evaporated. The nitric acid ultimately evaporated from the film. On the other hand, exposure of the SAM to HNO3 and H2O simultaneously gave only hydronium and nitrate ions. Molecular dynamics simulations of defective SAMs in the presence of HNO3 and water predict that nitric acid intercalates in defects as a complex with a single water molecule that is protected by alkyl chains from interacting with additional water molecules. These studies are consistent with the recently proposed hydrophobic nature of HNO3. Under atmospheric conditions, if HNO3 is formed in organic layers on surfaces in the boundary layer, e.g. through NO3 or N2O5 reactions, it may exist to a significant extent in its molecular form rather than fully dissociated to nitrate ions.

Nitrate and halide ions coexist in particles generated in marine regions, around alkaline dry lakes, and in the Arctic snowpack. Although the photochemistry of nitrate ions in bulk aqueous solution is well known, there is recent evidence that it may be more efficient at liquid–gas interfaces, and that the presence of other ions in solution may enhance interfacial reactivity. This study examines the 311 nm photolysis of thin aqueous films of ternary halide–nitrate salt mixtures (NaCl–NaBr–NaNO3) deposited on the walls of a Teflon chamber at 298 K. The films were generated by nebulizing aqueous 0.25 M NaNO3 solutions which had NaCl and NaBr added to vary the mole fraction of halide ions. Molar ratios of chloride to bromide ions were chosen to be 0.25, 1.0, or 4.0. The subsequent generation of gas phase NO2 and reactive halogen gases (Br2, BrCl and Cl2) were monitored with time. The rate of gas phase NO2 formation was shown to be enhanced by the addition of the halide ions to thin films containing only aqueous NaNO3. At [Cl−]/[Br−] ≤ 1.0, the NO2 enhancement was similar to that observed for binary NaBr–NaNO3 mixtures, while with excess chloride NO2 enhancement was similar to that observed for binary NaCl–NaNO3 mixtures. Molecular dynamics simulations predict that the halide ions draw nitrate ions closer to the interface where a less complete solvent shell allows more efficient escape of NO2 to the gas phase, and that bromide ions are more effective in bringing nitrate ions closer to the surface. The combination of theory and experiments suggests that under atmospheric conditions where nitrate ion photochemistry plays a role, the impact of other species such as halide ions should be taken into account in predicting the impacts of nitrate ion photochemistry.

Grease to grease – this is how one might begin to describe the tendency of hydrophobic stretches in protein amino acid sequences to form transmembrane domains. While this simple rule contains a lot of truth, the mechanisms of membrane protein folding, the insertion of hydrophobic protein domains into the lipid bilayer, and the apparent existence of highly polar residues in some proteins in the hydrophobic membrane core are subjects of lively debate – an indication that many details remain unresolved. Here, we present a historical survey of recent insights from experiments and computational studies into the rules and mechanisms of α-helical membrane protein assembly and stability.

Ambient pressure X-ray photoelectron spectroscopy (AP-XPS) was used to explore ion behavior at liquid/vapor interfaces of aqueous NaCl, RbCl, and RbBr solutions. Interfacial depth profiles of ions were obtained from XPS spectra at a series of photoelectron kinetic energies. Depth profiles of the ratio of anion to cation show little difference among the solutions. Previously, these depth profiles were determined from the ratio of anion to cation signal-peak areas. However, using molecular dynamics simulations (MD), the individual anion and cation depth profiles are both observed to differ as a function of solution, but the differences are masked when only the anion-to-cation ratios are considered. Using the Cl–/Owater ratio determined from the XPS measurements, surface-enhanced concentrations of Cl– are observed in the NaCl solution, but not in the RbCl solution, in agreement with predictions from MD simulations. We also report studies of aqueous solutions of RbBr. In contrast to an aqueous RbCl solution, our combination of AP-XPS experiments and MD simulations suggests that anion/cation ratios are enhanced at the surface for this system due to the separation of bromide and rubidium in the double layer near the surface, while the interfacial concentration of bromide does not differ considerably from the bulk.

We demonstrate that the driving forces for ion adsorption to the air–water interface for point charge models result from both cavitation and a term that is of the form of a negative electrochemical surface potential. We carefully characterize the role of the free energy due to the electrochemical surface potential computed from simple empirical models and its role in ionic adsorption within the context of dielectric continuum theory. Our research suggests that the electrochemical surface potential due to point charge models provides anions with a significant driving force for adsoprtion to the air–water interface. This is contrary to the results of ab initio simulations that indicate that the average electrostatic surface potential should favor the desorption of anions at the air–water interface. The results have profound implications for the studies of ionic distributions in the vicinity of hydrophobic surfaces and proteins.Keywords: dielectric continuum theory; free-energy; interfaces; ion solvation; statistical mechanics;

Nitrate ions commonly coexist with halide ions in aged sea salt particles, as well as in the Arctic snowpack, where NO3− photochemistry is believed to be an important source of NOy (NO + NO2 + HONO + ...). The effects of bromide ions on nitrate ion photochemistry were investigated at 298 ± 2 K in air using 311 nm photolysis lamps. Reactions were carried out using NaBr/NaNO3 and KBr/KNO3 deposited on the walls of a Teflon chamber. Gas phase halogen products and NO2 were measured as a function of photolysis time using long path FTIR, NOy chemiluminescence and atmospheric pressure ionization mass spectrometry (API-MS). Irradiated NaBr/NaNO3 mixtures show an enhancement in the rates of production of NO2 and Br2 as the bromide mole fraction (χNaBr) increased. However, this was not the case for KBr/KNO3 mixtures where the rates of production of NO2 and Br2 remained constant over all values of χKBr. Molecular dynamics (MD) simulations show that the presence of bromide in the NaBr solutions pulls sodium toward the solution surface, which in turn attracts nitrate to the interfacial region, allowing for more efficient escape of NO2 than in the absence of halides. However, in the case of KBr/KNO3, bromide ions do not appreciably affect the distribution of nitrate ions at the interface. Clustering of Br− with NO3− and H2O predicted by MD simulations for sodium salts may facilitate a direct intermolecular reaction, which could also contribute to higher rates of NO2 production. Enhanced photochemistry in the presence of halide ions may be important for oxides of nitrogen production in field studies such as in polar snowpacks where the use of quantum yields from laboratory studies in the absence of halide ions would lead to a significant underestimate of the photolysis rates of nitrate ions.

Several laboratories have carried out molecular dynamics (MD) simulations of arginine interactions with lipid bilayers and found that the energetic cost of placing arginine in lipid bilayers is an order of magnitude greater than observed in molecular biology experiments in which Arg-containing transmembrane helices are inserted across the endoplasmic reticulum membrane by the Sec61 translocon. We attempt here to reconcile the results of the two approaches. We first present MD simulations of guanidinium groups alone in lipid bilayers, and then, to mimic the molecular biology experiments, we present simulations of hydrophobic helices containing single Arg residues at different positions along the helix. We discuss the simulation results in the context of molecular biology results and show that the energetic discrepancy is reduced, but not eliminated, by considering free energy differences between Arg at the interface and at the center of the model helices. The reduction occurs because Arg snorkeling to the interface prevents Arg from residing in the bilayer center where the energetic cost of desolvation is highest. We then show that the problem with MD simulations is that they measure water-to-bilayer free energies, whereas the molecular biology experiments measure the energetics of partitioning from translocon to bilayer, which raises the fundamental question of the relationship between water-to-bilayer and water-to-translocon partitioning. We present two thermodynamic scenarios as a foundation for reconciliation of the simulation and molecular biology results. The simplest scenario is that translocon-to-bilayer partitioning is independent of water-to-bilayer partitioning; there is no thermodynamic cycle connecting the two paths.

The Symposium ‘Frontiers in membrane and membrane protein biophysics: experiments and theory’, held this year at the University of California, Irvine (August 19–20), celebrated the 70th Birthday of Stephen H. White by bringing together distinguished experimentalists and theoreticians to discuss the state of the art and future challenges in the field of membrane and membrane protein biophysics. The meeting and this special issue highlight the highly interdisciplinary nature of membrane and membrane protein biophysics, and the tremendous contributions that S. H. White and his lab have brought to the field.

There is increasing interest in the contribution of methyl groups to the overall dynamics measured by neutron scattering experiments of proteins. In particular an inflection observed in atomic mean square displacements measured as a function of temperature on high resolution spectrometers (∼1 μeV) was explained by the onset of methyl group rotations. By specifically labeling a non-methyl-containing side-chain in a native protein system, the purple membrane, and performing neutron scattering measurements, we here provide direct experimental evidence that the observed inflection is indeed due to methyl group rotations. Molecular dynamics simulations reproduce the experimental data, and their analysis suggests that the apparent transition is due to methyl group rotation entering the finite instrumental resolution of the spectrometer. Methyl group correlation times measured by solid state NMR in the purple membrane, taken from previous work, support the interpretation.

We have used a combination of temperature-programmed desorption (TPD) experiments and molecular dynamics (MD) simulations to characterize interactions between water and carboxylic acid-terminated surfaces. In the TPD experiments, D2O water interacts with alkylthiol self-assembled monolayers (SAMs) comprised of 3-mercaptopropionic acid (C3 acid), 15-mercaptopentadecaonic acid (C15 acid), 16-mercaptohexadenoic acid (C16 acid), or two-component monolayers of these constituents. Water TPD spectra exhibit broad, first-order desorption profiles with maximum desorption temperatures ranging from 168 K during desorption from the C16 acid to a maximum desorption temperature of 200 K when water desorbs from the C3 acid surface. For water desorption from the C15 acid and for the two-component surfaces, desorption traces adopt intermediate profiles between these two extremes. Desorption activation energies range from 42 and 50 kJ mol−1. In the MD studies, submonolayer concentrations of adsorbed water interact with slabs that simulate the one- and two-component SAMs employed in the TPD experiments as well as 4-mercaptobutanoic acid (C4 acid). The MD simulations are characterized by distributions of the water−carboxylic acid interaction energies and the orientation of the carbonyl groups. The water−carboxylic acid interaction energy distributions show excellent qualitative agreement with the desorption activation energy values determined from the TPD experiments. Analysis of the carbonyl group orientation from the MD simulations shows strong effects of SAM chain length and whether the SAM contains an odd or even number of carbon atoms. These “odd−even” and chain length effects support many of the results from the TPD experiments and the MD simulations. We discuss the effectiveness of employing MD simulations in concert with TPD studies as well as the atmospheric implications for the interaction of water with highly oxidized, multicomponent surfaces.

Sodium chloride solutions have been used extensively as a model of seawater in both theoretical and experimental studies of the chemistry of sea salt aerosol. Many groups have found that chloride anions are present at the air−solution interface. This observation has been important for the development of a mechanism for the heterogeneous production of molecular chlorine from chloride in sea salt aerosol. However, while sodium chloride is a major constituent of seawater, it is by no means the only salt present. Seawater contains one Mg2+ for every eight Na+. Mg2+ is naturally occurring in ocean waters from mineral deposits in the Earth’s crust and biological sources. Mg2+ forms a hexahydrate structure, rather than contact ion pairs with chloride anion, and this impacts the ordering of water in solution. In this study, we use molecular dynamics simulations, ab initio calculations, and vibrational sum frequency generation (SFG) spectroscopy to explore the effect of the Mg2+ cation and its tightly bound solvation shell on the surface propensity of chloride, ion−ion interactions, and water structure of the air−solution interface of concentrated chloride salt solutions. In addition, we provide molecular level details that may be relevant to the heterogeneous reactions of chloride in deliquesced sea salt aerosols. In particular, we show that the presence of the divalent Mg2+ cation does not modify the surface propensity of chloride compared to Na+ and hence, its availability to interfacial reaction, although some differences in the behavior of chloride may occur due to specific ion interactions. In this work, we also discuss the SFG free OH band at the surface of salt solutions and conclude that it is often not straightforward to interpret.

Magnesium dication plays many significant roles in biochemistry. While it is available to the environment from both ocean waters and mineral salts on land, its roles in environmental and atmospheric chemistry are still relatively unknown. Several pieces of experimental evidence suggest that contact ion pairing may not exist at ambient conditions in solutions of magnesium chloride up to saturation concentrations. This is not typical of most ions. There has been disagreement in the molecular dynamics literature concerning the existence of ion pairing in magnesium chloride solutions. Using a force field developed during this study, we show that contact ion pairing is not energetically favorable. Additionally, we present a concentration-dependent Raman spectroscopic study of the Mg−Owater hexaaquo stretch that clearly supports the absence of ion pairing in MgCl2 solutions, although a transition occurring in the spectrum between 0.06x and 0.09x suggests a change in solution structure. Finally, we compare experimental and calculated observables to validate our force field as well as two other commonly used magnesium force fields, and in the process show that ion pairing of magnesium clearly is not observed at higher concentrations in aqueous solutions of magnesium chloride, independent of the choice of magnesium force field, although some force fields give better agreement to experimental results than others.

Structural properties of large NO3−·(H2O)n (n = 15−500) clusters are studied by Monte Carlo simulations using effective fragment potentials (EFPs) and by classical molecular dynamics simulations using a polarizable empirical force field. The simulation results are analyzed with a focus on the description of hydrogen bonding and solvation in the clusters. In addition, a comparison between the electronic structure based EFP and the classical force field description of the 32 water cluster system is presented. The EFP simulations, which focused on the cases of n = 15 and 32, show an internal, fully solvated structure and a “surface adsorbed” structure for the 32 water cluster at 300 K, with the latter configuration being more probable. The internal solvated structure and the “surface adsorbed” structure differ considerably in their hydrogen bonding coordination numbers. The force field based simulations agree qualitatively with these results, and the local geometry of NO3− and solvation at the surface-adsorbed site in the force field simulations are similar to those predicted using EFPs. Differences and similarities between the description of hydrogen bonding of the anion in the two approaches are discussed. Extensive classical force field based simulations at 250 K predict that long time scale stability of “internal” NO3−, which is characteristic of extended bulk aqueous interfaces, emerges only for n > 300. Ab initio Møller−Plesset perturbation theory is used to test the geometries of selected surface and interior anions for n = 32, and the results are compared to the EFP and MD simulations. Qualitatively, all approaches agree that surface structures are preferred over the interior structures for clusters of this size. The relatively large aqueous clusters of NO3− studied here are of comparable size to clusters that lead to new particle formation in air. Nitrate ions on the surface of such clusters may have significantly different photochemistry than the internal species. The possible implications of surface-adsorbed nitrate ions for atmospheric chemistry are discussed.

Classical molecular dynamics simulations of aqueous solutions of sodium chloride and potassium fluoride at two different concentrations have been carried out using polarizable force fields and standard additive force fields (not including polarizability explicitly). We show that the presence of chloride ions at the air−solution interface, as predicted from the polarizable simulations of NaCl solutions, is reconcilable with the classical thermodynamics results of Gibbs absorption theory. We discuss the role of system size in the establishment of a bulklike region in which the ion densities have converged to the same value. We compare the results for NaCl solutions with those obtained for KF at two concentrations. We find that the computed surface tension and the surface excess follow the experimental trend for each salt solution. We have characterized the extent of adsorption by calculating the fraction of the solution surface area that is occupied by each ion. The analysis reveals that, as expected, in the KF solution neither the cation nor the anion is present on the surface, regardless of whether or not a polarizable force field is employed. On the other hand, in the NaCl solutions, chloride anions occupy the surface to an extent that is roughly proportional to their bulk concentration, but only when a polarizable model is used.

X-Ray photoemission spectroscopy operating under ambient pressure conditions is used to probe ion distributions throughout the interfacial region of a free-flowing aqueous liquid micro-jet of 6 M potassium fluoride. Varying the energy of the ejected photoelectrons by carrying out experiments as a function of X-ray wavelength measures the composition of the aqueous–vapor interfacial region at various depths. The F− to K+ atomic ratio is equal to unity throughout the interfacial region to a depth of 2 nm. The experimental ion profiles are compared with the results of a classical molecular dynamics simulation of a 6 M aqueous KF solution employing polarizable potentials. The experimental results are in qualitative agreement with the simulations when integrated over an exponentially decaying probe depth characteristic of an APPES experiment. First principles molecular dynamics simulations have been used to calculate the potential of mean force for moving a fluoride anion across the air–water interface. The results show that the fluoride anion is repelled from the interface, consistent with the depletion of F− at the interface revealed by the APPES experiment and polarizable force field-based molecular dynamics simulation. Together, the APPES and MD simulation data provide a detailed description of the aqueous–vapor interface of alkali fluoride systems. This work offers the first direct observation of the ion distribution at an aqueous potassium fluoride solution interface. The current experimental results are compared to those previously obtained for saturated solutions of KBr and KI to underscore the strong difference in surface propensity between soft/large and hard/small halide ions in aqueous solution.

We used MD simulations to investigate the dependence of the dynamics of a soluble protein, RNase A, on temperature and solvent environment. Consistent with neutron scattering data, the simulations predict that the protein undergoes a dynamical transition in both glycerol and aqueous solutions that is absent in the dry protein. The temperature of the transition is higher, while the rate of increase with temperature of the amplitudes of motion on the 100 ps timescale is lower, in glycerol versus water. Analysis of the dynamics of hydrogen bonds revealed that the protein dynamical transition is connected to the relaxation of the protein–solvent hydrogen bond network, which, in turn, is associated with solvent translational diffusion. Thus, it appears that the role of solvent dynamics in affecting the protein dynamical transition is qualitatively similar in water and glycerol.

Major recent advances: Results of molecular dynamics simulations with polarizable force fields, supported by surface sensitive experiments, indicate that the propensity of atomic and hydrophilic molecular ions for the air/water interface exhibits strong ion specificity. While hard, non-polarizable ions are repelled from the interface, soft, polarizable ions exhibit surface affinity.

•Chemical shift perturbations reveal ANS bindings local to the N-terminal domain and the adjacent interdomain interface.•Residue contacts from rigid docking are consistent with the solution NMR data.•γS-G18V exhibits more exposed hydrophobic patches in the N-terminal domain and at the interdomain interface than γS-WT.BackgroundThe objective of this study was to determine whether the cataract-related G18V variant of human γS-crystallin has increased exposure of hydrophobic residues that could explain its aggregation propensity and/or recognition by αB-crystallin.MethodsWe used an ANS fluorescence assay and NMR chemical shift perturbation to experimentally probe exposed hydrophobic surfaces. These results were compared to flexible docking simulations of ANS molecules to the proteins, starting with the solution-state NMR structures of γS-WT and γS-G18V.ResultsγS-G18V exhibits increased ANS fluorescence, suggesting increased exposed hydrophobic surface area. The specific residues involved in ANS binding were mapped by NMR chemical shift perturbation assays, revealing ANS binding sites in γS-G18V that are not present in γS-WT. Molecular docking predicts three binding sites that are specific to γS-G18V corresponding to the exposure of a hydrophobic cavity located at the interdomain interface, as well as two hydrophobic patches near a disordered loop containing solvent-exposed cysteines, all but one of which is buried in γS-WT.ConclusionsAlthough both proteins display non-specific binding, more residues are involved in ANS binding to γS-G18V, and the affected residues are localized in the N-terminal domain and the nearby interdomain interface, proximal to the mutation site.General significanceCharacterization of changes in exposed hydrophobic surface area between wild-type and variant proteins can help elucidate the mechanisms of aggregation propensity and chaperone recognition, presented here in the context of cataract formation. Experimental data and simulations provide complementary views of the interactions between proteins and the small molecule probes commonly used to study aggregation. This article is part of a Special Issue entitled Crystallin Biochemistry in Health and Disease.

Understanding the mechanism of G-protein coupled receptors action is of major interest for drug design. The visual rhodopsin is the prototype structure for the family A of G-protein coupled receptors. Upon photoisomerization of the covalently bound retinal chromophore, visual rhodopsins undergo a large-scale conformational change that prepares the receptor for a productive interaction with the G-protein. The mechanism by which the local perturbation of the retinal cis-trans isomerization is transmitted throughout the protein is not well understood. The crystal structure of the visual rhodopsin from squid solved recently suggests that a chain of water molecules extending from the retinal toward the cytoplasmic side of the protein may play a role in the signal transduction from the all-trans retinal geometry to the activated receptor. As a first step toward understanding the role of water in rhodopsin function, we performed a molecular dynamics simulation of squid rhodopsin embedded in a hydrated bilayer of polyunsaturated lipid molecules. The simulation indicates that the water molecules present in the crystal structure participate in favorable interactions with side chains in the interhelical region and form a persistent hydrogen-bond network in connecting Y315 to W274 via D80.

The light-induced isomerization of the retinal from 11-cis to all-trans triggers changes in the conformation of visual rhodopsins that lead to the formation of the activated state, which is ready to interact with the G protein. To begin to understand how changes in the structure and dynamics of the retinal are transmitted to the protein, we performed molecular dynamics simulations of squid rhodopsin with 11-cis and all-trans retinal, and with two different force fields for describing the retinal molecule. The results indicate that structural rearrangements in the binding pocket, albeit small, propagate toward the cytoplasmic side of the protein, and affect the dynamics of internal water molecules. The sensitivity of the active-site interactions on the retinal force-field parameters highlights the coupling between the retinal molecule and its immediate protein environment.

Voltage-dependent ion channels open and close in response to changes in membrane electrical potential due to the motion of their voltage-sensing domains (VSDs). VSD charge displacements within the membrane electric field are observed in electrophysiology experiments as gating currents preceding ionic conduction. The elementary charge motions that give rise to the gating current cannot be observed directly, but appear as discrete current pulses that generate fluctuations in gating current measurements. Here we report direct observation of gating-charge displacements in an atomistic molecular dynamics simulation of the isolated VSD from the KvAP channel in a hydrated lipid bilayer on the timescale (10-μs) expected for elementary gating charge transitions. The results reveal that gating-charge displacements are associated with the water-catalyzed rearrangement of salt bridges between the S4 arginines and a set of conserved acidic side chains on the S1–S3 transmembrane segments in the hydrated interior of the VSD.

Voltage-sensing domains (VSDs) of voltage-gated potassium (Kv) channels undergo a series of conformational changes upon membrane depolarization, from a down state when the channel is at rest to an up state, all of which lead to the opening of the channel pore. The crystal structures reported to date reveal the pore in an open state and the VSDs in an up state. To gain insights into the structure of the down state, we used a set of experiment-based restraints to generate a model of the down state of the KvAP VSD using molecular-dynamics simulations of the VSD in a lipid bilayer in excess water. The equilibrated VSD configuration is consistent with the biotin-avidin accessibility and internal salt-bridge data used to generate it, and with additional biotin-avidin accessibility data. In the model, both the S3b and S4 segments are displaced ∼10 Å toward the intracellular side with respect to the up-state configuration, but they do not move as a rigid body. Arginine side chains that carry the majority of the gating charge also make large excursions between the up and down states. In both states, arginines interact with water and participate in salt bridges with acidic residues and lipid phosphate groups. An important feature that emerges from the down-state model is that the N-terminal half of the S4 segment adopts a 310-helical conformation, which appears to be necessary to satisfy a complex salt-bridge network.

Atomistic molecular dynamics simulations are used to probe changes in the nature and subnanosecond dynamical behavior of solvation waters that accompany partial denaturation of the globular protein, human α-lactalbumin. A simulated ensemble of subcompact conformers, similar to the molten globule state of human α-lactalbumin, demonstrates a marginal increase in the amount of surface solvation relative to the native state. This increase is accompanied by subtle but distinct enhancement in surface water dynamics, less favorable protein-water interactions, and a marginal decrease in the anomalous behavior of solvation water dynamics. The extent of solvent influx is not proportional to the increased surface area, and the partially denatured conformers are less uniformly solvated compared to their native counterpart. The observed solvation in partially denatured conformers is lesser in extent compared to earlier experimental estimates in molten globule states, and is consistent with more recent descriptions based on nuclear magnetic relaxation dispersion studies.

The major removal processes for gaseous nitric acid (HNO3) in the atmosphere are dry and wet deposition onto various surfaces. The surface in the boundary layer is often covered with organic films, but the interaction of gaseous HNO3 with them is not well understood. To better understand the factors controlling the uptake of gaseous nitric acid and its dissociation in organic films, studies were carried out using single component and mixtures of C8 and C18 alkyl self-assembled monolayers (SAMs) attached to a germanium (Ge) attenuated total reflectance (ATR) crystal upon which a thin layer of SiOx had been deposited. For comparison, diffuse reflectance infrared Fourier transform spectrometry (DRIFTS) studies were also carried out using a C18 SAM attached to the native oxide layer on the surface of silicon powder. These studies show that the alkyl chain length and order/disorder of the SAMs does not significantly affect the uptake or dissociation/recombination of molecular HNO3. Thus, independent of the nature of the SAM, molecular HNO3 is observed up to 70–90% relative humidity. After dissociation, molecular HNO3 is regenerated on all SAM surfaces when water is removed. Results of molecular dynamics simulations are consistent with experiments and show that defects and pores on the surfaces control the uptake, dissociation and recombination of molecular HNO3. Organic films on surfaces in the boundary layer will certainly be more irregular and less ordered than SAMs studied here, therefore undissociated HNO3 may be present on surfaces in the boundary layer to a greater extent than previously thought. The combination of this observation with the results of recent studies showing enhanced photolysis of nitric acid on surfaces suggests that renoxification of deposited nitric acid may need to be taken into account in atmospheric models.

Nitric acid in air is formed by atmospheric reactions of oxides of nitrogen and is removed primarily through deposition to surfaces, either as the gas or after conversion to particulate nitrate. Many of the surfaces and particles have organic coatings, but relatively little is known about the interaction of nitric acid with organic films. We report here studies of the interaction of gaseous HNO3 with a self-assembled monolayer (SAM) formed by reacting 7-octenyltrichlorosilane [H2CCH(CH2)6SiCl3] with the surface of a germanium infrared-transmitting attenuated total reflectance (ATR) crystal that was coated with a thin layer of silicon oxide (SiOx). The SAM was exposed at 298 ± 2 K to dry HNO3 in a flow of N2, followed by HNO3 in humid N2 at a controlled relative humidity (RH) between 20–90%. For comparison, similar studies were carried out using a similar crystal without the SAM coating. Changes in the surface were followed using Fourier transform infared spectroscopy (FTIR). In the case of the SAM-coated crystal, molecular HNO3 and smaller amounts of NO3− ions were observed on the surface upon exposure to dry HNO3. Addition of water vapor led to less molecular HNO3 and more H3O+ and NO3− complexed to water, but surprisingly, molecular HNO3 was still evident in the spectra up to 70% RH. This suggests that part of the HNO3 observed was initially trapped in pockets within the SAM and shielded from water vapor. After increasing the RH to 90% and then exposing the film to a flow of dry N2, molecular nitric acid was regenerated, as expected from recombination of protons and nitrate ions as water evaporated. The nitric acid ultimately evaporated from the film. On the other hand, exposure of the SAM to HNO3 and H2O simultaneously gave only hydronium and nitrate ions. Molecular dynamics simulations of defective SAMs in the presence of HNO3 and water predict that nitric acid intercalates in defects as a complex with a single water molecule that is protected by alkyl chains from interacting with additional water molecules. These studies are consistent with the recently proposed hydrophobic nature of HNO3. Under atmospheric conditions, if HNO3 is formed in organic layers on surfaces in the boundary layer, e.g. through NO3 or N2O5 reactions, it may exist to a significant extent in its molecular form rather than fully dissociated to nitrate ions.

Nitrate and halide ions coexist in particles generated in marine regions, around alkaline dry lakes, and in the Arctic snowpack. Although the photochemistry of nitrate ions in bulk aqueous solution is well known, there is recent evidence that it may be more efficient at liquid–gas interfaces, and that the presence of other ions in solution may enhance interfacial reactivity. This study examines the 311 nm photolysis of thin aqueous films of ternary halide–nitrate salt mixtures (NaCl–NaBr–NaNO3) deposited on the walls of a Teflon chamber at 298 K. The films were generated by nebulizing aqueous 0.25 M NaNO3 solutions which had NaCl and NaBr added to vary the mole fraction of halide ions. Molar ratios of chloride to bromide ions were chosen to be 0.25, 1.0, or 4.0. The subsequent generation of gas phase NO2 and reactive halogen gases (Br2, BrCl and Cl2) were monitored with time. The rate of gas phase NO2 formation was shown to be enhanced by the addition of the halide ions to thin films containing only aqueous NaNO3. At [Cl−]/[Br−] ≤ 1.0, the NO2 enhancement was similar to that observed for binary NaBr–NaNO3 mixtures, while with excess chloride NO2 enhancement was similar to that observed for binary NaCl–NaNO3 mixtures. Molecular dynamics simulations predict that the halide ions draw nitrate ions closer to the interface where a less complete solvent shell allows more efficient escape of NO2 to the gas phase, and that bromide ions are more effective in bringing nitrate ions closer to the surface. The combination of theory and experiments suggests that under atmospheric conditions where nitrate ion photochemistry plays a role, the impact of other species such as halide ions should be taken into account in predicting the impacts of nitrate ion photochemistry.

X-Ray photoemission spectroscopy operating under ambient pressure conditions is used to probe ion distributions throughout the interfacial region of a free-flowing aqueous liquid micro-jet of 6 M potassium fluoride. Varying the energy of the ejected photoelectrons by carrying out experiments as a function of X-ray wavelength measures the composition of the aqueous–vapor interfacial region at various depths. The F− to K+ atomic ratio is equal to unity throughout the interfacial region to a depth of 2 nm. The experimental ion profiles are compared with the results of a classical molecular dynamics simulation of a 6 M aqueous KF solution employing polarizable potentials. The experimental results are in qualitative agreement with the simulations when integrated over an exponentially decaying probe depth characteristic of an APPES experiment. First principles molecular dynamics simulations have been used to calculate the potential of mean force for moving a fluoride anion across the air–water interface. The results show that the fluoride anion is repelled from the interface, consistent with the depletion of F− at the interface revealed by the APPES experiment and polarizable force field-based molecular dynamics simulation. Together, the APPES and MD simulation data provide a detailed description of the aqueous–vapor interface of alkali fluoride systems. This work offers the first direct observation of the ion distribution at an aqueous potassium fluoride solution interface. The current experimental results are compared to those previously obtained for saturated solutions of KBr and KI to underscore the strong difference in surface propensity between soft/large and hard/small halide ions in aqueous solution.