Effective Inclusion of Electronic Polarization Improves the Description of Electrostatic Interactions: The prosECCo75 Biomolecular Force Field.

prosECCo75 is an optimized force field effectively incorporating electronic polarization via charge scaling. It aims to enhance the accuracy of nominally nonpolarizable molecular dynamics simulations for interactions in biologically relevant systems involving water, ions, proteins, lipids, and saccharides. Recognizing the inherent limitations of nonpolarizable force fields in precisely modeling electrostatic interactions essential for various biological processes, we mitigate these shortcomings by accounting for electronic polarizability in a physically rigorous mean-field way that does not add to computational costs. With this scaling of (both integer and partial) charges within the CHARMM36 framework, prosECCo75 addresses overbinding artifacts. This improves agreement with experimental ion binding data across a broad spectrum of systems─lipid membranes, proteins (including peptides and amino acids), and saccharides─without compromising their biomolecular structures. prosECCo75 thus emerges as a computationally efficient tool providing enhanced accuracy and broader applicability in simulating the complex interplay of interactions between ions and biomolecules, pivotal for improving our understanding of many biological processes.

Hydrogen bond redistribution effects in mixtures of protic ionic liquids sharing the same cation: non-ideal mixing with large negative mixing enthalpies.

We report a joint experimental and theoretical study characterising the hydrogen bond (HB) redistribution in mixtures of two different protic ionic liquids (PILs) sharing the same cation: triethylammonium-methanesulfonate ([TEA][OMs]) and triethylammonium-trifluoromethanesulfonate ([TEA][OTf]). The mixing behaviour deviates strongly from ideality, exhibiting large negative energies of mixing. In the PIL, the [TEA] cation acts as a HB donor, being able to donate a single HB. Both, the [OMs] and the [OTf] anions can act as HB acceptors, which can accept multiple HBs via their respective SO3-groups. We use a combination of molecular dynamics (MD) simulations, calorimetry, and 1H-NMR chemical shift measurements to determine the difference in HB strength between the two species to be about 13 kJ mol-1, favouring the [TEA]-[OMs] interaction. Based on our MD simulations we are able to formulate a lattice model, discriminating between HB and nonspecific intermolecular interactions. We demonstrate that, due to the ordered structure of the PILs, mostly the HB interactions contribute to the mixing energy. This allows to us to connect the equilibrium of HBs to each of the two anion species with the mixing energies by a simple relation, which is obeyed by both, MD-simulation as well as experimental calorimetry and 1H-NMR chemical shift data.

Why Do Liquids Mix? The Mixing of Protic Ionic Liquids Sharing the Same Cation Is Apparently Driven by Enthalpy, Not Entropy.

We study hydrogen bond (HB) redistribution in mixtures of two protic ionic liquids (PILs) sharing the same cation: triethylammonium methanesulfonate ([TEA][OMs]) and triethylammonium trifluoromethanesulfonate ([TEA][OTf]). The mixtures exhibit large negative energies of mixing. Based on results obtained from atomic detail molecular dynamics (MD) simulations, we derive a lattice model, discriminating between HB and nonspecific intermolecular interactions. We demonstrate that due to the ordered structure of the PILs, mostly the HB interactions contribute to the mixing energy. This allows to us to connect the equilibrium of HBs to each of the two anion species with the corresponding excess energies and entropies. The entropy associated with HB redistribution is shown to be negative, and even overcompensating the positive entropy associated with a statistical distribution of the ions in the mixture. This is strongly suggesting that the mixing process is driven by enthalpy, not entropy.

Balance Between Contact and Solvent-Separated Ion Pairs in Mixtures of the Protic Ionic Liquid [Et3NH][MeSO3] with Water Controlled by Water Content and Temperature.

The formation of aggregates of ionic species is a crucial process in liquids and solutions. Ion speciation is particularly interesting for the case of ionic liquids (ILs) since these Coulombic fluids consist solely of ions. Most of their unique properties, such as enthalpies of vaporization and conductivities, are strongly related to ion pair formation. Here, we show that the balance of hydrogen-bonded contact ion pairs (CIP) and solvent-separated (SIP) ion pairs in protic ionic liquids (PILs) and in their mixtures with water can be well understood by a combination of far-infrared (FIR) and mid-infrared (MIR) spectroscopy, density functional theory (DFT) calculations of PIL/water aggregates, and molecular dynamics (MD) simulations of PIL/water mixtures. This combined approach is applied to mixtures of triethylammonium methanesulfonate [Et3NH][MeSO3] with water. It is shown that ion speciation in this mixture depends on three parameters: the relative hydrogen bond acceptor strength of the counter ion and the molecular solvent, the solvent concentration, and the temperature. For selected PIL/water mixtures, the equilibrium constants for CIPs and SIPs were determined as a function of the solvent content and temperature. Finally, for the studied PIL/water mixtures, the transition from CIPs to SIPs could be understood on enthalpic and entropic grounds. A detailed picture of this interconversion process could be described at the molecular level by means of MD simulations. In addition, the concentration dependence of ion pair formation can be well understood with help of a simplified "cartoon-like" statistical model describing hydrogen bond redistribution.

Thermodynamics of N-Isopropylacrylamide in Water: Insight from Experiments, Simulations, and Kirkwood-Buff Analysis Teamwork.

The behavior of thermoresponsive polymer poly(N-isopropylacrylamide) (PNiPAM), an essential building block in the design of smart soft materials, in aqueous solutions has attracted much interest, which contrasts with our knowledge of N-isopropylacrylamide (NiPAM) monomer. Strikingly, the physicochemical properties of aqueous NiPAM are similarly rich, and their understanding is far from being complete. This stems from the lack of accurate thermodynamic data and quantitative model for atomistic simulations. In this joint study, we have probed the thermodynamic behavior of aqueous NiPAM by experimental methods, molecular dynamics (MD) simulations, and Kirkwood-Buff (KB) analysis at ambient conditions. From the partial molar volumes and simultaneously correlated osmotic coefficients, with excess partial molar enthalpies of NiPAM in water, the concentration and temperature dependence of KB integrals was determined. For the purpose of this work, we have developed and employed a novel NiPAM force field, which not only reproduces KB integrals (Gij) and adequately captures macroscopic thermodynamic quantities but also provides more accurate structural insight than the original force fields. We revealed in the vicinity of NiPAM the competing effect of amide hydration with interaction between nonpolar regions. This microscopic picture is reflected in the experimentally observed NiPAM-NiPAM association, which is present from highly dilute conditions up to the solubility limit and is evidenced by G22. From intermediate concentrations, it is accompanied by the existence of apparent dense-water regions, as indicated by positive G11 values. The here-employed KB-based framework provided a mutually consistent thermodynamic and microscopic insight into the NiPAM solution and may be further extended for ion-specific effects. Moreover, our findings contribute to the understanding of thermodynamic grounds behind PNiPAM collapse transition.

Highly viscoelastic films at the water/air interface: α-Cyclodextrin with anionic surfactants.

This work showcases the remarkable viscoelasticity of films consisting of α-cyclodextrin (α-CD) and anionic surfactants (S) at the water/air interface, the magnitude of which has not been observed in similar systems. The anionic surfactants employed are sodium salts of a homologous series of n-alkylsulfates (n = 8-14) and of dodecylsulfonate. Our hypothesis was that the very high viscoelasticity can be systematically related to the bulk and interfacial properties of the system. Through resolution of the bulk distribution of species using isothermal titration calorimetry, the high dilatational modulus is related to (α-CD)2:S1 inclusion complexes in the bulk with respect to both the bulk composition and temperature. Direct interfacial characterization of α-CD and sodium dodecylsulfate films at 283.15 K using ellipsometry and neutron reflectometry reveals that the most viscoelastic films consist of a highly ordered monolayer of 2:1 complexes with a minimum amount of any other component. The orientation of the complexes in the films and their driving force for adsorption are discussed in the context of results from molecular dynamics simulations. These findings open up clear potential for the design of new functional materials or molecular sensors based on films with specific mechanical, electrical, thermal, chemical, optical or even magnetic properties.

Complex methodology for rational design of Apremilast-benzoic acid co-crystallization process.

A new co-crystal of pharmaceutical active ingredient Apremilast was successfully designed in this work. The discovered co-crystal with benzoic acid significantly improves key properties like the dissolution and stability of an otherwise poorly soluble Apremilast. A crystallization process was developed, which includes efficient solvent selection and ternary phase diagram construction to minimize risks during scale up. To increase efficiency, we propose that both steps be combined into a single methodology based on solubility data. A suitable solvent for the co-crystallization process was selected and ternary phase diagrams were constructed using three different modifications of thermodynamic model of solid-liquid equilibria. Based on the obtained information, the co-crystallization process was scaled-up to 100 mL. This provides a feasible process to produce larger amounts of this promising pharmaceutical solid form of Apremilast necessary for further drug development.

Molecular characterization of complete genome of a canine distemper virus associated with fatal infection in dogs in Gabon, Central Africa.

Canine distemper (CD) is the most deadly disease in dogs with mortality rates reaching 50%. The pathological agent, the CD virus (CDV), generally causes a severe systemic disease, although the nervous form can coexist with the acute catarrhal form in the same individual. In this study, we describe an outbreak of 18 cases of CD that occurred in 2015 in a German Shepherd dog population in northwestern Gabon. In addition, we determined the sequence of the CDV genotype associated with this fatal distemper infection in Gabon and compared it with other published CDV sequences. The CDV was detected using RT-PCR on cDNA from RNA of harvested brains and other organs. The identification was confirmed by sequencing amplicons. Moreover, we obtained the whole genome sequence using high-throughput sequencing. Phylogenetic analysis revealed that Gabonese CDV strain clustered with European strains belonging to the Europe genotype. This study provided the first molecular detection of the CDV strain associated with this fatal distemper infection in Central Africa region.

Complexation thermodynamics of α-cyclodextrin with ionic surfactants in water.

The interaction of α-cyclodextrin (α-CD) with ten ionic surfactants (S) in water was systematically examined using isothermal titration calorimetry. The S comprised cationic and anionic head groups while the hydrocarbon alkyl chain length varied from eight to fourteen carbon atoms. The heat data were measured at five temperatures ranging from 283.15K to 318.15K and were treated simultaneously allowing the estimation of a thermodynamically consistent temperature dependence of the equilibrium constant, as well as the enthalpy and heat capacity for the sequential formation of the [α-CD·S] and the [α-CD2·S] inclusion complexes. All attempts to fit the data assuming that only [α-CD·S] complexes are present failed. It was found that the thermodynamic footprint of the [α-CD·S] complexes does not depend importantly on the head group, while the formation and stabilization of the [α-CD2·S] complexes is strongly influenced by the chemical nature of the polar head group. Several contributions to the thermodynamic parameters are discussed in detail. Among the studied surfactants, the decyl- and octylsulfates were identified as those with a predominant content of [α-CD2·S] complexes and hence they are promising candidates to form viscoelastic films at the liquid/air interface, as it was found previously for the dodecylsulfate surfactant.

Interaction of ionic liquids ions with natural cyclodextrins.

The interaction of natural α-, ß-, and γ-cyclodextrins (CDs) with 14 hydrophobic ionic moieties of ionic liquids (ILs) was systematically examined in dilute aqueous solutions using isothermal titration microcalorimetry (ITC) and NMR spectroscopy. The studied cationic and anionic moieties involved some recently developed heavily fluorinated structures, as well as some others of common use. To isolate the effect of a given ion, the measurements were performed on salts containing the hydrophobic IL ion in question and a complexation-inactive counterion. Additional ITC experiments on ILs whose both cation and anion can interact appreciably with the CD cavity demonstrated that to resolve the effect of individual ions from such data is generally a tricky task and confirmed the superiority of the isolation strategy adopted for the purpose throughout this work. The binding constant, enthalpy and entropy determined at 298.15 K for the 1:1 (ion:CD) inclusion complex formation range in broad limits, being 0 < K < 2 × 10(5), 0 < -Δ(r)H°/(kJ·mol(-1)) < 44, and -28 < TΔ(r)S°/(kJ·mol(-1)) < 14, respectively. The stabilities of complexes of perfluorohexyl bearing ions with ß-CD belong to the highest ever observed with natural CDs in water. The established binding affinity scales were discussed in both thermodynamic and molecular terms. The concepts of hydrophobic interaction and guest-host size matching supported by simple molecular modeling proved useful to rationalize the observed widely different binding affinities and suggest possible binding modes. Enthalpy and entropy contributions to the stability of the ion-CD complexes were found to compensate each other considerably obeying more or less the linear compensation relationship marked by existing literature data on binding other guests to natural CDs. As outliers to this pattern, the most stable complexes of -C(6)F(13) bearing ions with ß-CD were found to receive an enhanced inherent entropy stabilization due to extraordinarily high extent of desolvation occurring in the course of binding.

Refined non-steady-state gas-liquid chromatography for accurate determination of limiting activity coefficients of volatile organic compounds in water: application to C(1)-C(5) alkanols.

This work presents a new refined method of non-steady-state gas-liquid chromatography (NSGLC) suitable for determination of limiting activity coefficients of VOCs in water. The modifications done to the original NSGLC theory address its elements (as the solvent elution rate from the column) as well as other new aspects. The experimental procedure is modified accordingly, taking advantage of current technical innovations. The refined method is used systematically to determine limiting activity coefficients (Henry's law constants, limiting relative volatilities) of isomeric C(1)-C(5) alkanols in water at 328.15K. Applied to retention data measured in this work the refined NSGLC theory gives values 15-20% higher than those from the original approach. The values obtained by the refined NSGLC method agree very well (typically within 3%) with the most reliable literature data determined by other experimental techniques, this result verifying thus the correct performance of the refined method and demonstrating an improved accuracy of the new results.