Final Report Summary - EXCHARGEHYD (The origin of excess charge at the water / hydrophobic interfaces) The aim of this project is the theoretical investigation of the salt adsorption process at the interface of water / hydrophobic substrates taking into account impurities, dissolved gases using thermodynamically consistent force fields for ions by molecular dynamic methods. Most hydrophobic polymer materials without any functional and reactive surface groups develop a substantial negative charge at their surface. Source of this excess charge is not determined yet, while the effect is enormous for electrically driven flows, in the context of electrical energy conversion, and it lies at the heart of many electrochemical and electrokinetic processes. Despite intensive theoretical and experimental efforts during past decades, this remarkable effect is still far from complete understanding. Molecular dynamic studies of water / hydrophobic substrate interfaces using atomistic force fields are challenging and can provide important information about the structure and dynamics of the environment and shed light on interface phenomena. However, explicit-solvent simulations require the definition of all forces acting between the individual atoms, and reliable results can only be obtained if the underlying force field parameters are realistic. The development of accurate force fields for condensed-phase simulations, especially in aqueous environment, is a complex problem. Using thermodynamically consistent force fields for ions can help to clarify interfacial effects involving ions. Therefore, first we have to design a model of ions that describes correctly several bulk properties of ions simultaneously. Traditionally, ion parameters were chosen in a somewhat unsystematic way to reproduce the solvation free energy and to give the correct ion size when compared with scattering results. Which experimental observable one chooses to reproduce should in principle depend on the context within which the ionic force field is going to be used. The force field parameters reported in the literature for divalent cations are mostly optimised based on single ion properties in solution or with respect to experimental data in the crystalline state. In practice however, these force fields often fail to reproduce electrolyte thermodynamic properties and ion specific effects at finite concentrations even for simple ionic solutions. Therefore, nowadays much attention is paid on the generation of force fields that can reproduce several thermodynamic properties of ionic solutions simultaneously at finite concentrations. During the reporting period, we developed force field parameters of the divalent cations Mg2+, Ca2+, Ba2+, and Sr2+. We performed molecular dynamic simulations with explicit water, using the simple point charge-extended (SPC / E) water model. The scheme we propose for the derivation of the ionic force fields is based on a simultaneous optimisation of single-ion and ion-pair properties. The solvation free energy and the effective radius of the divalent cations are the single ion properties used in our approach. As a probe for ion pair properties we compute the activity derivatives of salts in aqueous solutions. The optimisation of the ionic force fields was done in two consecutive steps. First, the solvation free energy and the first maximum in the ion-water Radial distribution function (RDF) were determined as a function of the Lennard-Jones (LJ) parameters used in the simulations. Second, the activity derivatives of the electrolytes, such as MgY2, CaY2, BaY2, SrY2, are determined through the Kirkwood-Buff theory, where Y=Cl-, Br-,I-. The activity derivatives are computed for restricted LJ parameters which reproduce the exact solvation free energy of the divalent cations. The optimal ion LJ parameters are those that lead to a value of the activity derivative closest to the respective experimental data. We have shown that for Ca2+, Ba2+ and Sr2+ such LJ parameters exist. On the other hand, for Mg2+ the experimental activity derivatives can only be reproduced if we generalise the combination rule for the anion-cation LJ interaction and rescale the effective cation-anion LJ radius, which is a modification that leaves the cation solvation free energy invariant. The cation force fields are transferable within acceptable accuracy, meaning the same cation force field is valid for all halide ions Cl-, Br-, I- tested in this study. In the next step we started to evaluate our newly generated force fields for transferability to interfacial environments and interactions with peptide molecules. We test the prediction of ion parameters with respect to interfacial properties of water in contact with air or with a hydrophobic self-assembled monolayer. There is no affinity of ions for the water / air and self-assembled monolayer / water interface, where we observe a negative surface excess. The question how strong exactly the cations are attracted to hydrophobic surfaces is still under study. Stability and solubility of proteins is important in development of biotechnology, chemical and pharmaceutical industry. Revealing the most effective cosolvents for structural stabilisation of proteins will improve the protein-based drug production and also enhance their storage and delivery capabilities. Ions have been shown to play an essential role in maintaining stability of peptides and greatly affect various properties including their activity, solubility, denaturation and dissociation to subunits. The denaturing ability of ions was separated into direct and indirect effects: direct binding to polar and nonpolar parts of the peptide surface, and indirect effects mediated by modification of the bulk water properties. Indirect effects, embodied in the change of solution activity as ions are added, are rarely monitored in salt / peptide simulations and thus have remained elusive in numerical studies. We established a rigorous separation of all three contributions to the solvation thermodynamics of stretched peptide chains. Together with bulk thermodynamic properties of salt / water mixed solvents, a complete thermodynamic description of the salt / water / peptide system is obtained. Simple thermodynamic arguments show that the indirect contribution to salt's denaturing capability is negligibly small, although salt essentially changes the water bulk properties as ions bind water molecules tightly and thus are strongly hydrated. Using Kirkwood-Buff theory we studied transfer free energies of peptides from pure water to aqueous NaCl, NaBr, KCl, KBr, MgCl2, CaCl2, guanidium chloride (GdmCl), guanidium sulfate (Gdm2SO4) solution. We separate direct and indirect effects to the transfer free energy of peptide molecule due to ions. The indirect effect is usually discussed in terms of water structure making or breaking. According to the general view, a structure breaking cosolute decreases the water structure and thus leads to better hydration of the peptide. Structure making cosolutes have the opposite effect and render the peptide hydration worse. The direct and indirect contribution to the transfer free energy was estimated through water and cosolvent excess per unit length of the peptide chain. It has been shown that NaCl and KCl precipitate protein from solution (salting-out), while KBr, NaBr, MgCl2, CaCl2 increase the solubility of protein and denature protein structure at c > 1M. Description of the main results achieved so far We developed force field parameters of most biologically active divalent cations Mg2+, Ca2+, Ba2+, and Sr2+ in conjunction with the SPC / E water model. We propose a new scheme for the derivation of the ionic force fields based on a simultaneous optimisation of single-ion and ion-pair properties. The solvation free energy and the effective radius of the divalent cations are the single ion properties used in our approach. As a probe for ion pair properties we compute the activity derivatives of salts in aqueous solutions. In this respect, the obtained optimised force fields for divalent cations are capable to describe the thermodynamic properties of single ions in water, as well as the electrolyte activity derivatives at finite ion concentrations in agreement with experimental data. - We test the predictions of our developed non-polarisable, thermodynamically consistent Mg2+, Ca2+, Ba2+, and Sr2+ ion parameters with respect to interfacial properties of water in contact with air and with a hydrophobic self-assembled monolayer. There is no affinity for the self-assembled monolayer / water interface, where we observe a negative surface excess. At this stage, the question how strong exactly a cation is attracted to hydrophobic surfaces remains unanswered. - Using Gibbs-Duhem relations we studied transfer free energies of peptides from pure water to aqueous GdmCl, Gdm2SO4, KCl, KBr, NaCl, CaCl2 solutions. We separate direct and indirect effects to the transfer free energy of peptide molecule due to ions. The indirect effect of ions is related to strengthening or breaking of the hydrogen-bonding network of water. The direct and indirect contribution to the transfer free energy was estimated through water and cosolvent excess per unit length of the peptide chain. The influence of ions to protein stability is explained on the basis of direct interactions of cations with the macromolecules and it is found that indirect contributions of ions are negligible small. It has been shown that GdmCl act as denaturant, whereas Gdm2SO4 does not have significant effect on protein stability. Expected final results and their potential impact and use (including the socio-economic impact and the wider societal implications of the project so far) At present time molecular dynamic simulations are not only important from an academic point of view but they also find use in pharmaceutical industry in drug design. To have accurate force-fields for biologically relevant ions (Mg2+, Sr2+, Ba2+, Ca2+) will thus lead to higher reliability of the simulated results. The optimised parameters are used within the project to study the adsorption of ions at non-polar surfaces and the effect of ions on stability and solubility of proteins. Molecular dynamic simulations in this area are challenging owing to the complex nature and inability of individual models to reproduce a wide variety of parameters for ions. Notably understanding the stability and solubility of proteins is important in development of biotechnologies, chemical and pharmaceutical industry.
