Solute-solvent Interactions Research Articles

Hybrid Cluster-Continuum Method for Single-Ion Solvation Free Energy in Acetonitrile Solvent.

A new hybrid discrete-continuum approach named the cluster-continuum static approximation (CCSA) has been proposed for acetonitrile solvent. The continuum part uses the conductor-like polarizable continuum model for electrostatic and a surface area-dependent term for nonelectrostatic solvation. The CCSA includes only one explicit acetonitrile solvent molecule and a damping function, which makes the CCSA method reduce to pure continuum solvation in the case of weaker potential of mean force for solute-solvent interaction. The performance of the model was tested for 22 anions and 22 cations, including challenge species that cannot be adequately described by pure continuum solvation. A comparison was done with the widely used solvent model density (SMD) model. For anions, the CCSA reduces to pure continuum solvation and the method has the same performance as the SMD model, with a standard deviation of the mean signed error (SD-MSE) of 2.7 kcal mol-1 for both models. However, the CCSA method for cations considerably outperforms the SMD model, with an SD-MSE of 3.3 kcal mol-1 for the former and 8.4 kcal mol-1 for the latter. The method can be automated, and the present study suggests that continuum solvation models could be parameterized taking into account the explicit solvation as proposed in this work.

Thermodynamic and Kinetic Behaviors of Electrolytes Mediated by Intermolecular Interactions Enabling High-Performance Lithium-Ion Batteries.

Electrolyte solvation chemistry regulated by lithium salts, solvents, and additives has garnered significant attention since it is the most effective strategy for designing high-performance electrolytes in lithium-ion batteries (LIBs). However, achieving a delicate balance is a persistent challenge, given that excessively strong or weak Li+-solvent coordination markedly undermines electrolyte properties, including thermodynamic redox stability and Li+-desolvation kinetics, limiting the practical applications. Herein, we elucidate the crucial influence of solvent-solvent interactions in modulating the Li+-solvation structure to enhance electrolyte thermodynamic and kinetic properties. As a paradigm, by combining strongly coordinated propylene carbonate (PC) with weakly coordinated cyclopentylmethyl ether (CPME), we identified intermolecular interactions between PC and CPME using 1H-1H correlation spectroscopy. Experimental and computational findings underscore the crucial role of solvent-solvent interactions in regulating Li+-solvent/anion interactions, which can enhance both the thermodynamic (i.e., antireduction capability) and kinetic (i.e., Li+-desolvation process) aspects of electrolytes. Additionally, we introduced an interfacial model to reveal the intricate relationship between solvent-solvent interactions, electrolyte properties, and electrode interfacial behaviors at a molecular scale. This study provides valuable insights into the critical impact of solvent-solvent interactions on electrolyte properties, which are pivotal for guiding future efforts in functionalized electrolyte engineering for metal-ion batteries.

Solvent accessible surface area-assessed molecular basis of osmolyte-induced protein stability.

In solvent-modulated protein folding, under certain physiological conditions, an equilibrium exists between the unfolded and folded states of the protein without any need to break or make a covalent bond. In this process, interactions between various protein groups (peptides) and solvent molecules are known to play a major role in determining the directionality of the chemical reaction. However, an understanding of the mechanism of action of the co(solvent) by a generic theoretical underpinning is lacking. In this study, a generic solvation model is developed based on statistical mechanics and the thermodynamic transfer free energy model by considering the microenvironment polarity of the interacting co(solvent)-protein system. According to this model, polarity and the fractional solvent-accessible surface areas contribute to the interaction energies. The present model includes various orientations of participating interactant solvent surfaces of suitable areas. As model systems, besides the backbone we consider naturally occurring amino acid residues solvated in ten different osmolytes, small organic compounds known to modulate protein stability. The present model is able to predict the correct trend of the osmolyte-peptide interactions ranging from stabilizing to destabilizing not only for the backbone but also for side chains. Our model predicts Asn, Gln, Asp, Glu, Arg and Pro to be highly stable in most of the protecting osmolytes while Ala, Val, Ile, Leu, Thr, Met, Lys, Phe, Trp and Tyr are predicted to be moderately stable, and Ser, Cys and Histidine are predicted to be least stable. However, in denaturing solvents, both backbone and side chain models show similar stabilities in urea and guanidine. One of the important aspects of this model is that it is essentially parameter-free and consistent with the electrostatics of the interaction partners that make this model suitable for estimating any solute-solvent interaction energies.

Toward an Understanding of Uric Acid Particle Dissolution: Surface and Bulk-Driven Water Activity.

Uric acid particles contribute to kidney stones, and natural processes for the elimination of stones depend on solute-solvent interactions. The process of uric acid dissolution has previously been understood via the lens of solubility; however, for pure and mixed salt solutions, these approaches do not provide a comprehensive picture of nanoscale particle solution thermodynamics. Unlike solubility measurements, water activity measurements provide us with information about the chemical potential responsible for the migration of water molecules driving the dissolution of particles. In this work, we used in situ experimental tools to estimate water activity values for pure uric acid aqueous droplets at different stages of droplet growth. The process of cloud formation, i.e., water condensation on a solute particle resulting in aqueous droplet formation, was leveraged to compare the water affinity for nanosized uric acid particles with a well-studied inorganic salt, sodium chloride. Specifically, we investigated microscopic uric acid particles (nanoparticles <300 nm, amorphous and super micron particles >5 μm, crystalline) and the mechanism of water uptake. The growth of droplet volume (Growth Factor, GF) for uric acid particles is experimentally observed for supermicrometer crystalline particles (>1 μm) at subsaturated humidity conditions (<100% RH). In addition, the water activity of submicrometer-size uric acid particles is estimated under subsaturated and supersaturated humidity conditions. These measurements provide us with information about the volume growth of droplets as water condenses in particles exposed to different humidity conditions. Our observations under subsaturated humidity conditions show that the uric acid particles have limited volume growth (<1% change per volume and <10% change per volume for crystalline and amorphous measurement, respectively). From the experimental data, the affinity of uric acid solute with water as a solvent is quantified in terms of water activity.

New approach: Solvent effects of benzaldehyde in aliphatic alcohol solvents with FT-IR spectroscopy and augmented vertex-adjacency matrices

In this study of benzaldehyde (BNZ) in 7 aliphatic alcohol solvents, were undertaken to investigate the solvent/solute interaction with Fouirer Transform Infrared Spectroscopy (FT-IR), BNZ produced carbonyl group stretching vibration frequencies (ν(C=O)1 and ν(C=O)2). In the present paper, ν(C=O)1 and ν(C=O)2 of BNZ are observed and correlated with the solvent acceptor number (AN), dipolarity/polarizability (π*), hydrogen-bond donor acidity (α), hydrogen-bond acceptor basicity (β), solvent polarity parameter [ET(30)], KBM parameter ƒ(ε), boiling point (bp) and the linear solvation energy relationship (LSER) using single and multiple regression analysis. All calculations were performed for ν(C=O)1 and ν(C=O)2 and compared. ν(C=O)1 was believed to correspond to a single hydrogen bonded BNZ-alcohol complex, while ν(C=O)2 was believed to correspond to a multiple hydrogen bonded BNZ-alcohol complex and multiple hydrogen-bonded alcohol molecules. It was seen that LSER equation as multiple regression analysis was better than single regression analysis in explaining solute-solvent interactions due to the higher correlation coefficients obtained. The correlations of a set of the mathematical characteristics of the augmented vertex-adjacency matrices (AV-AM) obtained by the chemical structure of BNZ with solvent parameters and ν(C=O) were investigated. It was determined that the correlation factors (R2 > 0.999) of the multiparameter regression models obtained using the matrix results were higher than the correlation factors (R2 > 0.99) of the LSER equations including solvent parameters.

Grain boundary segregation for the Fe-P system: Insights from atomistic modeling and Bayesian inference

In this work we re-assess experimental data for grain boundary (GB) segregation of P in bcc Fe with thermodynamic and statistical methods. The data are based on Auger-Electron-Spectroscopy (AES) measurements which have provided P GB concentrations for various bulk contents and temperatures for ferrite. While in the previous investigations of this system a single-site McLean equation was used to extract segregation enthalpy and entropy, we employ multi-site segregation models as suggested by atomistic simulations. We use a recently introduced methodology based on inter-atomic potentials to calculate the segregation energy spectrum, as well as vibrational entropy and solute-solute interactions of P in polycrystalline Fe, thereby obtaining a three-dimensional distribution of energy, entropy and interactions. Using this trivariate distribution we predict P GB concentrations and compare them to the experimental measurements. Furthermore, we calibrate the parameters of physical models of increasing complexity to the experimental data with an inverse modeling approach based on Bayesian inference. While it is not possible to seamlessly link the results from AES to atomistic modeling, our investigation provides significant new insights for thermodynamic modeling of GB segregation. The vibrational entropy deduced from experiment differs from physics based atomistic simulations even when taking the spectral nature of energy, entropy and interactions into account. However, the correlations of the quantities are in good agreement when considering the trivariate model. Our investigation highlights the need for new and more accurate experimental datasets of GB segregation.

Solubility measurements, correlations, DFT calculations, and thermodynamic properties of p-methylbenzyl alcohol in twelve organic solvents

This study had investigated the solubility of p-methylbenzyl alcohol (PMAL) by the static equilibrium method. Solubility data were determined in six common alcoholic solvents (methanol, ethanol, n-propanol, i-propanol, n-butanol, i-butanol) and non-alcoholic solvents (acetone, acetonitrile, ethyl formate, ethyl acetate, dichloromethane, 1,2-dichloroethane) over a temperature range of 278.15–313.15 K. The effect of temperature on PMAL solubility was significant in both solvent types, particularly in acetonitrile. Six thermodynamics models were employed to correlate the solubility data, with the modified Apelblat equation providing the best fit. The study also analyzed the factors influencing PMAL solubility by integrating the physicochemical properties of the solvents with Density Functional Theory calculations. The result suggested that multiple factors affect PMAL solubility in both solvent categories. Additionally, the electrostatic potential energy surfaces and the solvent–solute interaction energies were calculated based on Density Functional Theory. The order of interaction energies correlated with solubility trends. The calculated apparent thermodynamic properties, derived from the Van’t Hoff equation, revealed that the dissolution process was entropy-driven with heat absorption.

Solubility behavior and solvation effect of a photomechanical molecular crystal trans-4-chlorocinnamic acid in twelve neat solvents at temperatures from 283.15 to 323.15 K

Solubility of trans-4-chlorocinnamic acid as a photomechanical molecular crystal material in twelve pure solvents (water, ethanol, methanol, n-propanol, isopropanol, n-butanol, isobutanol, acetonitrile, 1,4-dioxane, acetone, methyl acetate and ethyl acetate) were measured from 283.15 to 325.15 K at 101.2 kPa. The results showed that the trans-4-chlorocinnamic acid solubility increased with the temperature, the order is: 1,4-dioxane > acetone > n-butanol > ethanol > n-propanol > isopropanol > isobutanol > methanol > methyl acetate > ethyl acetate > acetonitrile > water. Powder X-ray diffraction pattern (PXRD) and differential scanning calorimetry (DSC) were used to identify and characterize the equilibrated solid phase samples. The solubility behavior and the solute–solvent interaction of trans-4-chlorocinnamic acid in each selected mono-solvent were explored by the empirical solvents polarity parameter (ET(30)), hydrogen bonding, cohesive energy density, molecular structure, and Hansen solubility parameters (HSPs). In addition, the experimental solubility data were correlated by the modified Apelblat model and Yaws model, and the fitting results of this models were all satisfactory. The intermolecular forces were determined through molecular simulations, including Hirshfeld surface (HS) and Molecular Electrostatic Potential Surface (MEPS) analysis. The results showed that hydrogen bond can be formed between trans-4-chlorocinnamic acid and the selected solvents, which can help to further explain the dissolution behavior of trans-4-chlorocinnamic acid in the solvents.

Optical and electrochemical analysis of nitrogen-doped carbon quantum dots from Moosa balbeesiaana peels for advanced supercapacitor applications

The demand for suitable electrode materials for energy storage devices, driven by increasing energy needs and environmental concerns, has led to the investigation of green synthesis methods. In this study, a composite material (rGO@NCQDs) comprising nitrogen-doped carbon quantum dots (NCQDs) derived from Moosa balbeesiaana peels and reduced graphene oxide (rGO) was synthesized via hydrothermal methods to evaluate its photophysical properties and electrochemical performance for supercapacitors applications. Additionally, the electrochemical behavior of rGONCQDs combined with Vanadium pentoxide (V2O5) was explored.Characterization techniques including FTIR spectroscopy revealed typical carbon-based material features in rGO-decorated NCQDs, and rGONCQDs@V2O5 composite. SEM analysis illustrated distinctive surface structures (mushroom-shaped for rGO@NCQDs and flowered-shaped for rGONCQDs@V2O5), while XRD confirmed crystalline structures with specific sizes.Photophysical investigations demonstrated significant Solvatochromic shifts and strong solute-solvent interactions in the composites. Electrochemical studies, including cyclic Voltammetry and Galvanostatic measurements, exhibited promising performance metrics. Specifically, rGO@NCQDs demonstrated a specific capacitance of 134.68 Fg−1 with excellent retention over 5000 charge-discharge cycles. In contrast, rGONCQDs@V2O5 exhibited a maximum specific capacitance of 562.62 Fg−1 at a scan rate of 10 mVs−1 and exceptional cycle stability (96 % retention over 5000 cycles).These findings highlight the potential of the synthesized composites as efficient electrode materials for supercapacitors, offering enhanced electrochemical performance and stability. The study underscores the importance of green synthesis approaches in developing functional materials for sustainable energy storage applications.

Supramolecular self-assembly strategy for the enhanced solubility/dissolution rate and anti-cancer efficacy of osimertinib: Insights from multi-component crystals to drug chemistry

Multi-component crystal based on supramolecular self-assembly is an effective strategy to modify the physicochemical properties of poorly water-soluble drugs. In this study, eight novel multi-component crystals of Osimertinib (AZD) were firstly synthesized under the guidance of theoretical analysis. Five single crystals were successfully obtained, and the AZD-FMS cocrystal shows a distinctive structure wherein free FMS filled in the skeleton, which may be crucial for maintaining morphology. Analysis of crystal structures and Hirshfeld surfaces indicated the involvement of N−H···O and N···H−O hydrogen bonds in the multi-component crystals. Owing to robust intermolecular interactions, multi-component crystals exhibited improved solubility/dissolution rate compared to pure AZD. Multivariate analysis revealed coformers and strong solute–solvent interactions determined the solubility/dissolution rate. Multi-component crystals showed superior stability in solution and low humidity. Moreover, AZD-FSM increased 5.2-fold anti-tumor activity over AZD, which is anticipated to enhance efficacy, reduce drug toxicity, combat drug resistance, and transform from laboratory to clinical application.

Unlocking guanine’s potential: Unveiling electronic transitions and nanoelectronic applications through electric field modulation

Guanines, key players in DNA and RNA, exist as dynamic keto and enol forms, influencing reactivity and potential applications. This study explores the impact of external electric fields on these forms using computational methods in gas and solvent (water) phases. Analyzing the energy gap, dipole moment, enthalpy, and Gibbs free energy revealed distinct responses. The keto form showed a significant decrease in the energy gap in the presence of an electric field, particularly in water, indicating enhanced reactivity. Conversely, the enol form exhibited a stabilizing effect with increasing electric field strength. Thermodynamic properties highlighted solvent-dependent interactions and electric field-induced changes in electron density distribution. The study further investigated guanine’s potential for nanoelectronics by calculating I-V curves, revealing promising characteristics, especially for the keto form in the aqueous phase. Additionally, the analysis of solvation and cohesive energies provided insights into solute–solvent interactions and intrinsic molecular stability. Overall, this research contributes to understanding how guanine responds to electric fields, paving the way for novel guanine-based materials with potential applications in nanoelectronics.

Understanding the Vibrational Structure and Ultrafast Dynamics of the Metal Carbonyl Precatalyst [Mn(ppy)(CO)4

The solution phase structure, vibrational spectroscopy, and ultrafast relaxation dynamics of the precatalyst species [Mn(ppy)(CO)4] (1) in solution have been investigated using ultrafast two-dimensional infrared (2D-IR) spectroscopy. By comparing 2D-IR data with the results of anharmonic density functional theory (DFT) calculations, we establish an excellent agreement between measured and predicted inter-mode couplings of the carbonyl stretching vibrational modes of 1 that relates to the atomic displacements of axial and equatorial ligands in the modes and the nature of the molecular orbitals involved in M-CO bonding. Measurements of IR pump-probe spectra and 2D-IR spectra as a function of waiting time reveal the presence of ultrafast (few ps) intramolecular vibrational energy redistribution between carbonyl stretching modes prior to vibrational relaxation. The vibrational relaxation times of the CO-stretching modes of 1 are found to be relatively solvent-insensitive, suggestive of limited solvent-solute interactions in the ground electronic state. Overall, these data provide a detailed picture of the complex potential energy surface, bonding and vibrational dynamics of 1, establishing a fundamental basis for the next steps in understanding and modulating precatalyst behavior.

Volumetric and Viscosity Properties for the Dilute Solution of [Bmim][OAc] in NMP and the Solute–Solvent Interaction from 288.15 to 318.15 K

Volumetric and Viscosity Properties for the Dilute Solution of [Bmim][OAc] in NMP and the Solute–Solvent Interaction from 288.15 to 318.15 K

Multi-temperature charge scaling of ionic solvents: Disparate responses of thermodynamic properties

Charge scaling as a treatment to effectively include the intermolecular charge transfer and polarization effects is widely applied in molecular modelling of ionic solvents. While the charge scaling factor of 0.8 is picked as a generally applicable solution usable in many computational works, in this work based on extremely precise molecular simulations of bulk solvents and nonequilibrium Hamiltonian switching, we highlight the fact that the general 0.8 selection of the charge scaling factor could be a solution specific to the room-temperature condition that most ionic-liquids studies perform. When the environmental condition varies, this ‘general’ recommendation could sometimes lead to huge deviations. The situation is further complicated by the disparate responses of different properties (bulk density and solvation free energy) in the charge scaling space and along the temperature ladder. The driving force triggering the disparate responses could be attributed to the difference between interaction components involved in different thermodynamic properties, i.e., solvent–solvent interactions for bulk density and the additional solute–solvent interaction in the solvation process. A caution hinted by these observations is the necessity of condition- and property-specific parameter adjustment in practical situations.

Investigation on the Influence of Solvents Environment on the Optoelectronic Properties of the Fluorescent Probe 1,3,4-Oxadiazole Analogues: A Combined Theoretical and Experimental Study.

This study investigates the photophysical properties of a nitrobenzene-substituted 1,3,4-oxadiazole derivative (OX-NO) using both theoretical and experimental methods. The impact of the solvent on OX-NO absorption and fluorescence spectra, as well as its fluorescence quantum yield, was initially studied. A noticeable bathochromic shift in the Stokes shift indicated a π→ π* transition within the molecules. Solute-solvent interactions were analysed using Catalan parameters, distinguishing between specific and nonspecific interactions. Excited state dipole moments were derived from Lippert's, Bakshiev's, and Chamma Viallet's equations, showing increased polarity in the excited state compared to the ground state. Ground state dipole moments were determined via solvatochromic shift methods and ab initio techniques. Additionally, detailed analyses of bond length, angles, dihedral angles, Mulliken charge distribution, and HOMO-LUMO energy gap were conducted using the DFT-B3LYP-6-311G basis set in Gaussian-09W. The energy band gap values obtained from theoretical calculations and experimental methods (cyclic voltammetry and UV-Visible spectroscopy) exhibited excellent agreement. Reactive sites such as electrophilic and nucleophilic regions were identified through total electron density, electrostatic maps, molecular electrostatic potential, and 3D plots using DFT computational analysis. Global descriptors were employed to characterize the compounds' chemical reactivity comprehensively. The observed photophysical attributes underscore the potential of these fluorophores in various applications like organic light-emitting diodes, solar cells, and chemosensors. This study contributes crucial insights into the optoelectronic properties of nitrobenzene-substituted 1,3,4-oxadiazole derivatives, paving the way for their future integration in advanced technological domains.

Insight into the Manipulation Mechanism of Polymorphic Transformation by Polymers: A Case of Cimetidine.

Employing polymer additives is an effective strategy to realize the manipulation of polymorphic transformation. However, the manipulation mechanism is still not clear, which limit the precise selection of polymeric excipients and the development of pharmaceutical formulations. The solubility of cimetidine (CIM) in acetonitrile/water mixtures were measured. And the polymorphic transformation from CIM form A to form B with the addition of different polymers was monitored by Raman spectroscopy. Furthermore, the manipulation effect of polymers was determined based on the results of experiments and molecular simulations. The solubility of form A is consistently higher than that of form B, which indicate that form B is the thermodynamically stable form within the examined temperature range. The presence of polyvinylpyrrolidone (PVP) of a shorter chain length could have a stronger inhibitory effect on the phase transformation process of metastable form, whereas polyethylene glycol (PEG) had almost no impact. The nucleation kinetics experiments and molecular dynamic simulation results showed that only PVP molecules could significantly decrease the nucleation rate of CIM, due to the ability of reducing solute molecular diffusion and solute-solute molecular interaction. A combination of crystal growth rate measurements and calculations of the interaction energies between PVP and the crystal faces of CIM indicate that smaller molecular weight PVP can suppress crystal growth more effectively. PVP K16-18 has more impact on the stabilization of CIM form A and inhibition of the phase transformation process. The manipulation mechanism of polymer additives in the polymorphic transformation of CIM was proposed.

Solubility determination, model evaluation, molecular simulation and thermodynamic analysis of Dehydroacetic acid in thirteen pure solvents

The solid–liquid equilibrium solubility of DHA in thirteen pure solvents (methanol, ethanol, n-propanol, isopropanol, n-pentanol, ethyl formate, ethyl acetate, N, N-dimethyl acetamide (DMA), N, N-dimethyl formamide (DMF), acetonitrile, acetone, 2-butanone, dimethyl sulfoxide (DMSO)) was determined at temperatures ranging from 288.15–323.15 K under local atmosphere by gravimetric method. The experimental results showed that the solubility of DHA was positively correlated with the rising of temperatures. Five thermodynamic models, including Ideal model, Apelblat model, λh model, NRTL model and Wilson model, were employed to fit the experimental data and Wilson model provided a better correlation. The KAT-LSER model and molecular dynamic simulations were also carried out to investigate the effects of solvent–solute interactions on solubility. Furthermore, the thermodynamic properties of the dissolution process were calculated and the results argued a spontaneous, exothermic and entropy-driven process.

Unveiling the conformational landscape of tizanidine and its effects on selective nucleation: Enabling controlled manipulation of polymorphs and solvates

The intricate relationship between conformational diversity and polymorphic nucleation is evident, while the underlying mechanisms remain unclear. In this work, tizanidine (TZND) was selected as the model compound to investigate its selective nucleation behavior and the association between conformations and polymorphs. Crystallization experiments were conducted using TZND in seven solvents, resulting in two polymorphs and four solvates, five of which are reported for the first time. Quantum chemical calculations were employed to explore the conformational landscape of TZND. Furthermore, 2D nuclear Overhauser effect spectroscopy and molecular dynamics were utilized to analyze the predominant conformation and its evolution in different solvents with varying concentrations. The results revealed that the dominant conformation of TZND could nucleate directly in methanol and acetone, while a conformational transition occurred during nucleation in acetonitrile and dichloromethane. Additionally, proton transfer in DMSO, chloroform, and DMF resulted in the emergence of new conformational forms. Moreover, crystallographic analysis, spectroscopic studies and quantum chemical calculations were adopted to investigate the molecular mechanisms governing selective nucleation and the formation of polymorphs or solvates. The results indicated that the free energy and solute–solvent interaction energy at specific sites influence the dominant conformation and its evolution in the solution. Finally, the nucleation mechanisms of different polymorphs and solvates were proposed and discussed, illustrating an efficient and environmentally friendly regulation method through solvent switching.

Tracking Prenucleation Molecular Clustering of Salicylamide in Organic Solvents.

Crystal nucleation shapes the structure and product size distribution of solid-state pharmaceuticals and is seeded by early-stage molecular self-assemblies formed in host solution. Here, molecular clustering of salicylamide in ethyl acetate, methanol, and acetonitrile was investigated using photon correlation spectroscopy. Cluster size steadily increased over 3 days and with concentration across the range from undersaturated to supersaturated solutions. Solute concentration normalized by solubility provided more sensitive characterization of molecular-level conditions than concentration alone. In saturated solution, cluster size is independent of solvent, while at equal supersaturation, solvent-dependent cluster size increases as methanol < acetonitrile < ethyl acetate, commensurate with increasing nucleation propensity. In ethyl acetate, with largest prenucleation clusters, the driving force required for nucleation is lowest, compared to methanol with smallest clusters and highest driving force. To understand solvent-solute effects, we performed IR spectroscopy supported by molecular simulations. We observe solute-solvent interaction weakening in the same order: methanol < acetonitrile < ethyl acetate, quantifying the weaker solvent-solute interactions that permit the formation of larger prenucleation clusters. Our results support the hypothesis that nucleation is easier in weaker solvents because weak solute-solvent interactions favor growth of large clusters, as opposed to relying solely on ease of desolvation.

Scrutinising the Conformational Ensemble of the Intrinsically Mixed-Folded Protein Galectin-3.

Galectin-3 is a protein involved in many intra- and extra-cellular processes. It has been identified as a diagnostic or prognostic biomarker for certain types of heart disease, kidney disease and cancer. Galectin-3 comprises a carbohydrate recognition domain (CRD) and an N-terminal domain (NTD), which is unstructured and contains eight collagen-like Pro-Gly-rich tandem repeats. While the structure of the CRD has been solved using protein crystallography, current knowledge about conformations of full-length galectin-3 is limited. To fill in this knowledge gap, we performed molecular dynamics (MD) simulations of full-length galectin-3. We systematically re-scaled the solute-solvent interactions in the Martini 3 force field to obtain the best possible agreement between available data from SAXS experiments and the ensemble of conformations generated in the MD simulations. The simulation conformations were found to be very diverse, as reflected, e.g., by (i) large fluctuations in the radius of gyration, ranging from about 2 to 5 nm, and (ii) multiple transient contacts made by amino acid residues in the NTD. Consistent with evidence from NMR experiments, contacts between the CRD and NTD were observed to not involve the carbohydrate-binding site on the CRD surface. Contacts within the NTD were found to be made most frequently by aromatic residues. Formation of fuzzy complexes with unspecific stoichiometry was observed to be mediated mostly by the NTD. Taken together, we offer a detailed picture of the conformational ensemble of full-length galectin-3, which will be important for explaining the biological functions of this protein at the molecular level.