Building Water Models Compatible with Charge Scaling Molecular Dynamics.

Charge scaling has proven to be an efficient way to account in a mean-field manner for electronic polarization by aqueous ions in force field molecular dynamics simulations. However, commonly used water models with dielectric constants over 50 are not consistent with this approach leading to "overscaling", i.e., generally too weak ion-ion interactions. Here, we build water models fully compatible with charge scaling, i.e., having the correct low-frequency dielectric constant of about 45. To this end, we employ advanced optimization and machine learning schemes in order to explore the vast parameter space of four-site water models efficiently. As an a priori unwarranted positive result, we find a sizable range of force field parameters that satisfy the above dielectric constant constraint providing at the same time accuracy with respect to experimental data comparable with the best existing four-site water models such as TIP4P/2005, TIP4P-FB, or OPC. The present results thus open the way to the development of a consistent charge scaling force field for modeling ions in aqueous solutions.

Stability and Reactivity of Aromatic Radical Anions in Solution with Relevance to Birch Reduction.

We investigate the electronic structure of aromatic radical anions in the solution phase employing a combination of liquid-jet (LJ) photoelectron (PE) spectroscopy measurements and electronic structure calculations. By using recently developed protocols, we accurately determine the vertical ionization energies of valence electrons of both the solvent and the solute molecules. In particular, we first characterize the pure solvent of tetrahydrofuran (THF) by LJ-PE measurements in conjunction with ab initio molecular dynamics simulations and G0W0 calculations. Next, we determine the electronic structure of neutral naphthalene (Np) and benzophenone (Bp) as well as their radical anion counterparts Np- and Bp- in THF. Wherever feasible, we performed orbital assignments of the measured PE features of the aromatic radical anions, with comparisons to UV-vis absorption spectra of the corresponding neutral molecules being instrumental in rationalizing the assignments. Analysis of the electronic structure differences between the neutral species and their anionic counterparts provides understanding of the primarily electrostatic stabilization of the radical anions in solution. Finally, we obtain a very good agreement of the reduction potentials extracted from the present LJ-PES measurements of Np- and Bp- in THF with previous electrochemical data from cyclic voltammetry measurements. In this context, we discuss how the choice of solvent holds significant implications for optimizing conditions for the Birch reduction process, wherein aromatic radical anions play crucial roles as reactive intermediates.

Hydration numbers of biologically relevant divalent metal cations from ab initio molecular dynamics and continuum solvation methods.

Hydration and, in particular, the coordination number of a metal ion is of paramount importance as it defines many of its (bio)physicochemical properties. It is not only essential for understanding its behavior in aqueous solutions but also determines the metal ion reference state and its binding energy to (bio)molecules. In this paper, for divalent metal cations Ca2+, Cd2+, Cu2+, Fe2+, Hg2+, Mg2+, Ni2+, Pb2+, and Zn2+, we compare two approaches for predicting hydration numbers: (1) a mixed explicit/continuum DFT-D3//COSMO-RS solvation model and (2) density functional theory based ab initio molecular dynamics. The former approach is employed to calculate the Gibbs free energy change for the sequential hydration reactions, starting from [M(H2O)2]2+ aqua complexes to [M(H2O)9]2+, allowing explicit water molecules to bind in the first or second coordination sphere and determining the most stable [M(H2O)n]2+ structure. In the latter approach, the hydration number is obtained by integrating the ion-water radial distribution function. With a couple of exceptions, the metal ion hydration numbers predicted by the two approaches are in mutual agreement, as well as in agreement with the experimental data.

Hydration of biologically relevant tetramethylammonium cation by neutron scattering and molecular dynamics.

Neutron scattering and molecular dynamics studies were performed on a concentrated aqueous tetramethylammonium (TMA) chloride solution to gain insight into the hydration shell structure of TMA, which is relevant for understanding its behavior in biological contexts of, e.g., properties of phospholipid membrane headgroups or interactions between DNA and histones. Specifically, neutron diffraction with isotopic substitution experiments were performed on TMA and water hydrogens to extract the specific correlation between hydrogens in TMA (HTMA) and hydrogens in water (HW). Classical molecular dynamics simulations were performed to help interpret the experimental neutron scattering data. Comparison of the hydration structure and simulated neutron signals obtained with various force field flavors (e.g. overall charge, charge distribution, polarity of the CH bonds and geometry) allowed us to gain insight into how sensitive the TMA hydration structure is to such changes and how much the neutron signal can capture them. We show that certain aspects of the hydration, such as the correlation of the hydrogen on TMA to hydrogen on water, showed little dependence on the force field. In contrast, other correlations, such as the ion-ion interactions, showed more marked changes. Strikingly, the neutron scattering signal cannot discriminate between different hydration patterns. Finally, ab initio molecular dynamics was used to examine the three-dimensional hydration structure and thus to benchmark force field simulations. Overall, while neutron scattering has been previously successfully used to improve force fields, in the particular case of TMA we show that it has only limited value to fully determine the hydration structure, with other techniques such as ab initio MD being of a significant help.

From the outer ear to the nerve: A complete computer model of the peripheral auditory system.

Computer models of the individual components of the peripheral auditory system - the outer, middle, and inner ears and the auditory nerve - have been developed in the past, with varying level of detail, breadth, and faithfulness of the underlying parameters. Building on previous work, we advance the modeling of the ear by presenting a complete, physiologically justified, bottom-up computer model based on up-to-date experimental data that integrates all of these parts together seamlessly. The detailed bottom-up design of the present model allows for the investigation of partial hearing mechanisms and their defects, including genetic, molecular, and microscopic factors. Also, thanks to the completeness of the model, one can study microscopic effects in the context of their implications on hearing as a whole, enabling the correlation with neural recordings and non-invasive psychoacoustic methods. Such a model is instrumental for advancing quantitative understanding of the mechanism of hearing, for investigating various forms of hearing impairment, as well as for devising next generation hearing aids and cochlear implants.

Nonaqueous Ion Pairing Exemplifies the Case for Including Electronic Polarization in Molecular Dynamics Simulations.

The inclusion of electronic polarization is of crucial importance in molecular simulations of systems containing charged moieties. When neglected, as often done in force field simulations, charge-charge interactions in solution may become severely overestimated, leading to unrealistically strong bindings of ions to biomolecules. The electronic continuum correction introduces electronic polarization in a mean-field way via scaling of charges by the reciprocal of the square root of the high-frequency dielectric constant of the solvent environment. Here, we use ab initio molecular dynamics simulations to quantify the effect of electronic polarization on pairs of like-charged ions in a model nonaqueous environment where electronic polarization is the only dielectric response. Our findings confirm the conceptual validity of this approach, underlining its applicability to complex aqueous biomolecular systems. Simultaneously, the results presented here justify the potential employment of weaker charge scaling factors in force field development.

Common Cations Are Not Polarizable: Effects of Dispersion Correction on Hydration Structures from Ab Initio Molecular Dynamics.

We employed density functional theory-based ab initio molecular dynamics simulations to examine the hydration structure of several common alkali and alkali earth metal cations. We found that the commonly used atom pairwise dispersion correction scheme D3, which assigns dispersion coefficients based on the neutral form of the atom rather than its actual oxidation state, leads to inaccuracies in the hydration structures of these cations. We evaluated this effect for lithium, sodium, potassium, and calcium and found that the inaccuracies are particularly pronounced for sodium and potassium compared to the experiment. To remedy this issue, we propose disabling the D3 correction specifically for all cation-including pairs, which leads to a much better agreement with experimental data.

Curvature Matters: Modeling Calcium Binding to Neutral and Anionic Phospholipid Bilayers.

In this work, the influence of membrane curvature on the Ca2+ binding to phospholipid bilayers is investigated by means of molecular dynamics simulations. In particular, we compared Ca2+ binding to flat, elastically buckled, or uniformly bent zwitterionic and anionic phospholipid bilayers. We demonstrate that Ca2+ ions bind preferably to the concave membrane surfaces in both types of bilayers. We also show that the membrane curvature leads to pronounced changes in Ca2+ binding including differences in free ion concentrations, lipid coordination distributions, and the patterns of ion binding to different chemical groups of lipids. Moreover, these effects differ substantially for the concave and convex membrane monolayers. Comparison between force fields with either full or scaled charges indicates that charge scaling results in reduction of the Ca2+ binding to curved phosphatidylserine bilayers, while for phosphatidylcholine membranes, calcium binds only weakly for both force fields.

Effects of Water Deuteration on Thermodynamic and Structural Properties of Proteins and Biomembranes.

Light and heavy water are often used interchangeably in spectroscopic experiments with the tacit assumption that the structure of the investigated biomolecule does not depend too much on employing one or the other solvent. While this may often be a good approximation, we demonstrate here using molecular dynamics simulations incorporating nuclear quantum effects via modification of the interaction potential that there are small but significant differences. Namely, as quantified and discussed in the present study, both proteins and biomembranes tend to be slightly more compact and rigid in D2O than in H2O, which reflects the stronger hydrogen bonding in the former solvent.

Gas phase C6H6 - anion: Electronic stabilization by opening of the benzene ring.

It is well established that an isolated benzene radical anion is not electronically stable. In the present study, we experimentally show that electron attachment to benzene clusters leads to weak albeit unequivocal occurrence of a C6H6 - moiety. We propose here-based on electronic structure calculation-that this moiety actually corresponds to linear structures formed by the opening of the benzene ring via electron attachment. The cluster environment is essential in this process since it quenches the internal energy released upon ring opening, which in the gas phase leads to further dissociation of this anion.

Bridging Electrochemistry and Photoelectron Spectroscopy in the Context of Birch Reduction: Detachment Energies and Redox Potentials of Electron, Dielectron, and Benzene Radical Anion in Liquid Ammonia.

Birch reduction is a time-proven way to hydrogenate aromatic hydrocarbons (such as benzene), which relies on the reducing power of electrons released from alkali metals into liquid ammonia. We have succeeded to characterize the key intermediates of the Birch reduction process─the solvated electron and dielectron and the benzene radical anion─using cyclic voltammetry and photoelectron spectroscopy, aided by electronic structure calculations. In this way, we not only quantify the electron binding energies of these species, which are decisive for the mechanism of the reaction, but also use Birch reduction as a case study to directly connect the two seemingly unrelated experimental techniques.

Ionic Strength and Solution Composition Dictate the Adsorption of Cell-Penetrating Peptides onto Phosphatidylcholine Membranes.

Adsorption of arginine-rich positively charged peptides onto neutral zwitterionic phosphocholine (PC) bilayers is a key step in the translocation of those potent cell-penetrating peptides into the cell interior. In the past, we have shown both theoretically and experimentally that polyarginines adsorb to the neutral PC-supported lipid bilayers in contrast to polylysines. However, comparing our results with previous studies showed that the results often do not match even at the qualitative level. The adsorption of arginine-rich peptides onto 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) may qualitatively depend on the actual experimental conditions where binding experiments have been performed. In this work, we systematically studied the adsorption of R9 and K9 peptides onto the POPC bilayer, aided by molecular dynamics (MD) simulations and fluorescence cross-correlation spectroscopy (FCCS) experiments. Using MD simulations, we tested a series of increasing peptide concentrations, in parallel with increasing Na+ and Ca2+ salt concentrations, showing that the apparent strength of adsorption of R9 decreases upon the increase of peptide or salt concentration in the system. The key result from the simulations is that the salt concentrations used experimentally can alter the picture of peptide adsorption qualitatively. Using FCCS experiments with fluorescently labeled R9 and K9, we first demonstrated that the binding of R9 to POPC is tighter by almost 2 orders of magnitude compared to that of K9. Finally, upon the addition of an excess of either Na+ or Ca2+ ions with R9, the total fluorescence correlation signal is lost, which implies the unbinding of R9 from the PC bilayer, in agreement with our predictions from MD simulations.

Electronic structure of the solvated benzene radical anion.

The benzene radical anion is a molecular ion pertinent to several organic reactions, including the Birch reduction of benzene in liquid ammonia. The species exhibits a dynamic Jahn-Teller effect due to its open-shell nature and undergoes pseudorotation of its geometry. Here, we characterize the complex electronic structure of this condensed-phase system based on ab initio molecular dynamics simulations and GW calculations of the benzene radical anion solvated in liquid ammonia. Using detailed analysis of the molecular and electronic structure, we find that the spatial character of the excess electron of the solvated radical anion follows the underlying Jahn-Teller distortions of the molecular geometry. We decompose the electronic density of states to isolate the contribution of the solute and to examine the response of the solvent to its presence. Our findings show the correspondence between instantaneous molecular structure and spin density; provide important insights into the electronic stability of the species, revealing that it is, indeed, a bound state in the condensed phase; and offer electronic densities of states that aid in the interpretation of experimental photoelectron spectra.

Photoelectron Spectroscopy of Benzene in the Liquid Phase and Dissolved in Liquid Ammonia.

We report valence band photoelectron spectroscopy measurements of gas-phase and liquid-phase benzene as well as those of benzene dissolved in liquid ammonia, complemented by electronic structure calculations. The origins of the sizable gas-to-liquid-phase shifts in electron binding energies deduced from the benzene valence band spectral features are quantitatively characterized in terms of the Born-Haber solvation model. This model also allows to rationalize the observation of almost identical shifts in liquid ammonia and benzene despite the fact that the former solvent is polar while the latter is not. For neutral solutes like benzene, it is the electronic polarization response determined by the high frequency dielectric constant of the solvent, which is practically the same in the two liquids, that primarily determines the observed gas-to-liquid shifts.

The glycine arginine-rich domain of the RNA-binding protein nucleolin regulates its subcellular localization.

Nucleolin is a multifunctional RNA Binding Protein (RBP) with diverse subcellular localizations, including the nucleolus in all eukaryotic cells, the plasma membrane in tumor cells, and the axon in neurons. Here we show that the glycine arginine rich (GAR) domain of nucleolin drives subcellular localization via protein-protein interactions with a kinesin light chain. In addition, GAR sequences mediate plasma membrane interactions of nucleolin. Both these modalities are in addition to the already reported involvement of the GAR domain in liquid-liquid phase separation in the nucleolus. Nucleolin transport to axons requires the GAR domain, and heterozygous GAR deletion mice reveal reduced axonal localization of nucleolin cargo mRNAs and enhanced sensory neuron growth. Thus, the GAR domain governs axonal transport of a growth controlling RNA-RBP complex in neurons, and is a versatile localization determinant for different subcellular compartments. Localization determination by GAR domains may explain why GAR mutants in diverse RBPs are associated with neurodegenerative disease.

Anisotropic diffusion of membrane proteins at experimental timescales.

Single-particle tracking (SPT) experiments of lipids and membrane proteins provide a wealth of information about the properties of biomembranes. Careful analysis of SPT trajectories can reveal deviations from ideal Brownian behavior. Among others, this includes confinement effects and anomalous diffusion, which are manifestations of both the nanoscale structure of the underlying membrane and the structure of the diffuser. With the rapid increase in temporal and spatial resolution of experimental methods, a new aspect of the motion of the particle, namely, anisotropic diffusion, might become relevant. This aspect that so far received only little attention is the anisotropy of the diffusive motion and may soon provide an additional proxy to the structure and topology of biomembranes. Unfortunately, the theoretical framework for detecting and interpreting anisotropy effects is currently scattered and incomplete. Here, we provide a computational method to evaluate the degree of anisotropy directly from molecular dynamics simulations and also point out a way to compare the obtained results with those available from SPT experiments. In order to probe the effects of anisotropic diffusion, we performed coarse-grained molecular dynamics simulations of peripheral and integral membrane proteins in flat and curved bilayers. In agreement with the theoretical basis, our computational results indicate that anisotropy can persist up to the rotational relaxation time [τ=(2Dr)-1], after which isotropic diffusion is observed. Moreover, the underlying topology of the membrane bilayer can couple with the geometry of the particle, thus extending the spatiotemporal domain over which this type of motion can be detected.

Spectroscopic evidence for a gold-coloured metallic water solution.

Insulating materials can in principle be made metallic by applying pressure. In the case of pure water, this is estimated1 to require a pressure of 48 megabar, which is beyond current experimental capabilities and may only exist in the interior of large planets or stars2-4. Indeed, recent estimates and experiments indicate that water at pressures accessible in the laboratory will at best be superionic with high protonic conductivity5, but not metallic with conductive electrons1. Here we show that a metallic water solution can be prepared by massive doping with electrons upon reacting water with alkali metals. Although analogous metallic solutions of liquid ammonia with high concentrations of solvated electrons have long been known and characterized6-9, the explosive interaction between alkali metals and water10,11 has so far only permitted the preparation of aqueous solutions with low, submetallic electron concentrations12-14. We found that the explosive behaviour of the water-alkali metal reaction can be suppressed by adsorbing water vapour at a low pressure of about 10-4 millibar onto liquid sodium-potassium alloy drops ejected into a vacuum chamber. This set-up leads to the formation of a transient gold-coloured layer of a metallic water solution covering the metal alloy drops. The metallic character of this layer, doped with around 5 × 1021 electrons per cubic centimetre, is confirmed using optical reflection and synchrotron X-ray photoelectron spectroscopies.

Benzene Radical Anion Microsolvated in Ammonia Clusters: Modeling the Transition from an Unbound Resonance to a Bound Species.

The benzene radical anion, well-known in organic chemistry as the first intermediate in the Birch reduction of benzene in liquid ammonia, exhibits intriguing properties from the point of view of quantum chemistry. Notably, it has the character of a metastable shape resonance in the gas phase, while measurements in solution find it to be experimentally detectable and stable. In this light, our previous calculations performed in bulk liquid ammonia explicitly reveal that solvation leads to stabilization. Here, we focus on the transition of the benzene radical anion from an unstable gas-phase ion to a fully solvated bound species by explicit ionization calculations of the radical anion solvated in molecular clusters of increasing size. The computational cost of the largest systems is mitigated by combining density functional theory with auxiliary methods including effective fragment potentials or approximating the bulk by polarizable continuum models. Using this methodology, we obtain the cluster size dependence of the vertical binding energy of the benzene radical anion converging to the value of -2.3 eV at a modest computational cost.

Heavy Water Models for Classical Molecular Dynamics: Effective Inclusion of Nuclear Quantum Effects.

Small differences in physical and chemical properties of H2O and D2O, such as melting and boiling points or pKa, can be traced back to a slightly stronger hydrogen bonding in heavy versus normal water. In particular, deuteration reduces zero-point vibrational energies as a demonstration of nuclear quantum effects. In principle, computationally demanding quantum molecular dynamics is required to model such effects. However, as already demonstrated by Feynmann and Hibbs, zero-point vibrations can be effectively accounted for by modifying the interaction potential within classical dynamics. In the spirit of the Feymann-Hibbs approach, we develop here two water models for classical molecular dynamics by fitting experimental differences between H2O and D2O. We show that a three-site SPCE-based model accurately reproduces differences between properties of the two water isotopes, with a four-site TIP4P-2005/based model in addition capturing also the absolute values of key properties of heavy water. The present models are computationally simple enough to allow for extensive simulations of biomolecules in heavy water relevant, for example, for experimental techniques such as NMR or neutron scattering.

Sweet taste of heavy water.

Hydrogen to deuterium isotopic substitution has only a minor effect on physical and chemical properties of water and, as such, is not supposed to influence its neutral taste. Here we conclusively demonstrate that humans are, nevertheless, able to distinguish D2O from H2O by taste. Indeed, highly purified heavy water has a distinctly sweeter taste than same-purity normal water and can add to perceived sweetness of sweeteners. In contrast, mice do not prefer D2O over H2O, indicating that they are not likely to perceive heavy water as sweet. HEK 293T cells transfected with the TAS1R2/TAS1R3 heterodimer and chimeric G-proteins are activated by D2O but not by H2O. Lactisole, which is a known sweetness inhibitor acting via the TAS1R3 monomer of the TAS1R2/TAS1R3, suppresses the sweetness of D2O in human sensory tests, as well as the calcium release elicited by D2O in sweet taste receptor-expressing cells. The present multifaceted experimental study, complemented by homology modelling and molecular dynamics simulations, resolves a long-standing controversy about the taste of heavy water, shows that its sweet taste is mediated by the human TAS1R2/TAS1R3 taste receptor, and opens way to future studies of the detailed mechanism of action.