Free Energy Of Transfer Research Articles

The Entropy of Mixing in Self-Assembly and the Role of Surface Tension in Modeling the Critical Micelle Concentration

A theory for the micelle formation of nonionic head-tail amphiphiles (detergents) in aqueous solutions is derived based on the traditional molecular thermodynamic modeling approach and a variant of the Flory–Huggins theory that goes beyond lattice models. The theory is used to analyze experimental values for the critical micelle concentration of n-alkyl-ß-D-maltosides within a mass action model. To correlate those parts of the micellization free energy, which depend on the transfer of hydrophobic molecule parts into the aqueous phase, with molecular surfaces, known data for the solubility of alkanes in water are reanalyzed. The correct surface tension to be used in connection with the solvent-excluded surface of the alky tail is ~30 mN/m. This value is smaller than the measured surface tension of a macroscopic alkane–water interface, because the transfer free energy contains a contribution from the incorporation of the alkane or alkyl chain into water, representing the change in free volume in the aqueous phase. The Flory–Huggins theory works well, if one takes into account the difference in liberation free energy between micelles and monomers, which can be described in terms of the aggregation number as well as the thermal de Broglie wavelength and the free volume of the detergent monomer.

Aggregation behavior, interaction forces and physico-chemical parameters of cetyltrimethylammonium chloride in aqueous solution of bovine serum albumin: Impacts of short-chain alcohols and temperature

To better understand the molecular interactions between cetyltrimethylammonium chloride (CTAC) and bovine serum albumin (BSA), we report the alteration of the physicochemical characteristics of CTAC in aqueous BSA solutions in the presence of different alcohols. The analyses were performed using the conductivity method at temperatures ranging from 298.15 to 323.15 K, with 5 K intervals. The critical micelle concentration (CMC) values of the BSA + CTAC systems were found to change with variations in alcohol types, solvent compositions, and temperatures. The CMC values grew with the rising of alcohol contents. The negative free energy changes (∆Gm0) indicated the spontaneous association of the systems in all solvents media. The magnitudes of ∆Hm0 and ∆Sm0, determined from the micellization of the systems, indicated the presence of electrostatic, ion-dipole, and hydrophobic forces. The thermodynamics of transfer (free energy (∆Gm,tr0), enthalpy (∆Hm,tr0), entropy (∆Sm,tr0)), and compensation parameters (∆Hm0,∗ and Tc)—were also calculated, which provided significant insights into the potential interactions between CTAC and BSA in the presence of various alcohol additives. Furthermore, molecular docking studies suggested the binding of CTAC to different BSA binding sites with varying affinities.

Molecular Insights of 5-Hydroxymethylfurfural in a Mixture of Ionic Liquids and Alkylated Phenolic Solvents.

This paper presents all-atom molecular dynamics to understand the separation behavior of 5-hydroxymethylfurfural (5-HMF) from 1-butyl-3-methylimidazolium tetrafluoroborate [BMIM]+[BF4]- using alkylated phenols as extractants. We have utilized four solvents such as 4-methyl phenol (4-MP), 4-ethyl phenol (4-EP), 4-propyl phenol (4-PP), and 4-butyl phenol (4-BP). We perform structural, dynamic, and rigorous thermodynamic analyses of 5-HMF in the mixture of ILs and solvents. The [BMIM]+[BF4]- show a strong interaction with phenols. The self-diffusion coefficient of 5-HMF shows a 3-fold increase with a decrease in the methyl group on the phenol. The solvation-free energy (ΔGsolvation) of 5-HMF shows favorably in phenols. On the other hand, the transfer free energy (ΔGtransfer) of 5-HMF presents favorable from ILs to phenols. The partition coefficient (log P) values show favorability for separation of 5-HMF using phenols. Overall, the molecular level analysis provides the role of the alkyl group effect on the phenols for extracting 5-HMF from the ILs.

Hydronium Ion Transport across the Liquid/Liquid Interface Assisted by a Phase-Transfer Catalyst: Structure and Thermodynamics Using Molecular Dynamics Simulation.

Molecular dynamics simulations are used to examine the thermodynamic and structural aspects of the transfer of the classical hydronium ion (H3O+) across a water/1,2-dichloroethane (DCE) interface assisted by the phase-transfer catalyst (PTC) tetrakis(pentafluorophenyl) borate anion (TPFB-). The free energy of transfer from water to DCE of the H3O+-TPFB- ion pair is calculated to be 6 ± 1 kcal/mol, significantly less than that of the free hydronium ion (17 ± 1 kcal/mol). The ion pair is relatively stable at the interface and in the organic phase when it is accompanied by three water molecules with a small barrier to dissociation that supports its utility as a PTC. An examination of the hydration structure that accompanies the transfer of the ion pair shows that the ion pair, like the free hydronium ion, is transferred with the assistance of a finger-like water structure.

The Analytical Theory of Water Activity in the Paddy Rice Drying Process

Drying involves the evaporation of moisture, accompanied by simultaneous heat transfer, mass transfer, and momentum transfer. While the diffusion law is considered an applicable model for explaining the drying phenomenon, the actual drying process cannot be accurately predicted using an analytical solution with a constant diffusion coefficient. Energy efficiency in the drying process is low due to an insufficient understanding of the mechanisms governing moisture migration from solids to air. The development of drying theory has stalled due to an unsolvable discrepancy between experimental results and analytical results. This study analyzes the effect of the binding energy of moisture in paddy rice on the diffusion coefficient. The theoretical relationship between water activity and drying rate in paddy rice was investigated, and the drying process was successfully explained by analyzing free energy transfer and transition theory. The mechanism of rice grain drying was described using a new theoretical solution for the drying process. These results provide new insights into the development of a scientific evaluation standard for assessing the efficiency of actual drying processes.

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.

Molecular simulation of understanding the structure and separation thermodynamics of BTX (Benzene, Toluene, Xylene) using amino acid based ionic liquids

The separation of aromatics and aliphatic from the hydrocarbon mixture stands a significant challenge. In this manuscript we present atomistic molecular dynamic simulations to understand the structure and separation thermodynamic properties of BTX (Benzene, toluene, xylene) from n-heptane using ionic liquids. Here we considered the amino acid derived ionic liquid considering the tetra butyl phosphonium as cation and valine anion at three different temperatures 298 K, 323 K and 348 K. We observe that IL show strong intermolecular structure with BEN (benzene) when compared to TOL (toluene) and XYL (p-xylene). Based on the solvation free energy (ΔGsolv), transfer free energy (ΔGtransfer) and partition coefficient (log P) analysis of BEN show favourable for the transfer from n-heptane to IL phase when compared to TOL and XYL. Overall results presented in this paper provide molecular level understanding of the design of amino acid-based IL for the separation BTX from the hydrocarbon mixture.

Double quenching electrochemiluminescence aptsensor based on free radical elimination and resonance energy transfer for the sensitive detection of zearalenonea

Zearalenone (ZEN) has serious impacts on human and animal health due to its mutagenicity, teratogenicity, carcinogenicity, immunotoxicity, and genetic toxicity. In this study, an electrochemiluminescence (ECL) aptsensor for ultrasensitive ZEN detection was constructed based on the double quenching effect of CM-MOFs. Luminol was fixed on the gold nanoparticle-modified Prussian blue analogs (Au NPs@PBAs) with catalytic activity by Au-NH2 to obtain Lu@Au@PBAs with stable and strong signal output. Bimetallic porphyrin metal-organic frameworks (CM-MOFs) improve the sensitivity of aptsensors through radical elimination and resonance energy transfer strategies. The experimental data shows that the dynamic detection range of the aptsensor is 500 fg/mL∼100 ng/mL, and the limit of detection is as low as 0.37 pg/mL. The aptsensor is proven to be suitable for the detection of ZEN in corn flour and has strong practicability. It is important that the ECL detection strategy can be used to detect other similar analytes and has a wide range of potential applications in food analytical detection.

Synergetic FeMoSe@NiCo-LDH hybrid heterostructures as a stable and effective bifunctional catalyst for sustained overall water splitting and seawater splitting

Designing cost-effective and highly active and stable earth-abundant-based bifunctional electrocatalysts for oxygen evolution reaction (OER) and hydrogen evolution reaction (HER) is significant, yet challenging task. In this work, we employed synergetic design of FeMoSe@NiCo-LDH heterostructures electrocatalyst to effectively enhance OER and HER performance in the alkaline media by addressing the lethargic kinetics. Combining FeMoSe and NiCo-LDH components as hybrid heterostructure promotes synergistic effects inherently, and influences adsorption free energy and charge transfer, and improves overall reaction kinetics and durability. The FeMoSe@NiCo-LDH hybrid heterostructure catalyst demonstrates low overpotential of 240 mVRHE for OER and 170 mVRHE for HER to drive 10 mA cm−2 in high-pH media. Upon integration into two electrode electrolysers, the synergetic FeMoSe@NiCo-LDH electrocatalyst delivers a stable cell voltage is 1.71 V (overall seawater splitting) and 1.65 V (overall water splitting), stability at 10 mA cm−2, demonstrating its spectacular bifunctional activity, commendable for the sustainable hydrogen generation. The FeMoSe@NiCo-LDH catalyst exemplifies an economically viable and environmentally sustainable approach for hydrogen generation on larger scale.

Martini-Based Coarse-Grained Soil Organic Matter Model Derived from Atomistic Simulations.

The significance of soil organic matter (SOM) in environmental contexts, particularly its role in pollutant adsorption, has prompted an increased utilization of molecular simulations to understand microscopic interactions. This study introduces a coarse-grained SOM model, parametrized within the framework of the versatile Martini 3 force field. Utilizing models generated by the Vienna Soil Organic Matter Modeler 2, which constructs humic substance systems from a fragment database, we employed Swarm-CG to parametrize the fragments and subsequently assembled them into macromolecules. Direct Boltzmann inversion (DBI) facilitated the determination of bonded parameters between fragments. The parametrization yielded favorable agreement in the radius of gyration and solvent-accessible surface area. Transfer free energies exhibited a strong correlation with hexadecane-water and chloroform-water values, albeit deviations were noted for octanol-water values. Comparing densities of modeled Leonardite humic acid systems at coarse-grained and atomistic levels revealed promising agreement, particularly at higher water concentrations. The DBI approach effectively reproduced average values of bonded interactions between fragments. Radial distribution functions between carboxylate groups and calcium ions showed partial agreement, however, reproducing certain peaks was challenging due to fixed bead sizes. Detailed analysis of atomistic systems revealed different configurations between the groups, explaining discrepancies. The present contribution provides a comprehensive insight into the properties, strengths, and weaknesses of the coarse-grained SOM model, serving as a foundation for future investigations encompassing pollutant interactions and varied SOM compositions.

Quantitative entropy-enthalpy compensation in intraprotein interactions from model compound data.

Many small globular proteins exist in only two states-the physiologically relevant folded state and an inactive unfolded state. The active state is stabilized by numerous weak attractive contacts, including hydrogen bonds, other polar interactions, and the hydrophobic effect. Knowledge of these interactions is key to understanding the fundamental equilibrium thermodynamics of protein folding and stability. We focus on one such interaction, that between amide and aromatic groups. We provide a statistically convincing case for quantitative, linear entropy-enthalpy compensation in forming aromatic-amide interactions using published model compound transfer-free energy data.

Towards understanding the crystallization of photosystem II: influence of poly(ethylene glycol) of various molecular sizes on the micelle formation of alkyl maltosides.

The influence of poly(ethylene glycol) (PEG) polymers H-(O-CH2-CH2)p-OH with different average molecular sizes on the micelle formation of n-alkyl-β-D-maltoside detergents with the number of carbon atoms in the alkyl chain ranging from to is investigated with the aim to learn more about the detergent behavior under conditions suitable for the crystallization of the photosynthetic pigment-protein complex photosystem II. PEG is shown to increase the critical micelle concentration (CMC) of all three detergents in the crystallization buffer in a way that the free energy of micelle formation increases linearly with the concentration of oxyethylene units (O-CH2-CH2) irrespective of the actual molecular weight of the polymer. The CMC shift is modeled by assuming for simplicity that it is dominated by the interaction between PEG and detergent monomers and is interpreted in terms of an increase of the transfer free energy of a methylene group of the alkyl chain by 0.2kJmol-1 per 1mol L-1 increase of the concentration of oxyethylene units at 298K. Implications of this effect for the solubilization and crystallization of protein-detergent complexes as well as detergent extraction from crystals are discussed.

In Silico Analysis of Natural Plant-Derived Cyclotides with Antifungal Activity against Pathogenic Fungi.

Fungal infections in plants, animals, and humans are widespread across the world. Limited classes of antifungal drugs to treat fungal infections and loss of drug efficacy due to rapidly evolving fungal strains pose a challenge in the agriculture and health sectors. Hence, the search for a new class of antifungal agents is imperative. Cyclotides are cyclic plant peptides with multiple bioactivities, including antifungal activity. They have six conserved cysteine residues forming three disulfide linkages (CI-CIV, CII-CV, CIII-CVI) that establish a Cyclic Cystine Knot (CCK) structure, making them extremely resistant to chemical, enzymatic, and thermal attacks. This in silico analysis of natural, plant-derived cyclotides aimed to assess the parameters that can assist and hasten the process of selecting the cyclotides with potent antifungal activity and prioritize them for in vivo/ in vitro experiments. The objective of this study was to conduct in silico studies to compare the physicochemical parameters, sequence diversity, surface structures, and membrane-cyclotide interactions of experimentally screened (from literature survey) potent (MIC ≤ 20 μM) and non-potent (MIC > 20 μM) cyclotides for antifungal activity. Cyclotide sequences assessed for antifungal activity were retrieved from the database (Cybase). Various online and offline tools were used for sequence-based studies, such as physicochemical parameters, sequence diversity, and neighbor-joining trees. Structure-based studies involving surface structure analysis and membrane-cyclotide interaction were also carried out. All investigations were conducted in silico. Physicochemical parameter values, viz. isoelectric point, net charge, and the number of basic amino acids, were significantly higher in potent cyclotides compared to non-potent cyclotides. The surface structure of potent cyclotides showed a larger hydrophobic patch with a higher number of hydrophobic amino acids. Furthermore, the membrane-cyclotide interaction studies of potent cyclotides revealed lower transfer free energy (ΔG transfer) and higher penetration depth into fungal membranes, indicating higher binding stability and membrane-disruption ability. These in silico studies can be applied for rapidly identifying putatively potent antifungal cyclotides for in vivo and in vitro experiments, which will ultimately be relevant in the agriculture and pharmaceutical sectors.

Transfer free energy predicts osmolyte-induced structural and functional changes in intrinsically disordered proteins

Transfer free energy predicts osmolyte-induced structural and functional changes in intrinsically disordered proteins

Development and test of highly accurate endpoint free energy methods. 3: partition coefficient prediction using a Poisson-Boltzmann method combined with a solvent accessible surface area model for SAMPL challenges.

Accurately predicting solvation free energy is the key to predict protein-ligand binding free energy. In addition, the partition coefficient (log P), which is an important physicochemical property that determines the distribution of a drug in vivo, can be derived directly from transfer free energies, i.e., the difference between solvation free energies (SFEs) in different solvents. Within the Statistical Assessment of the Modeling of Proteins and Ligands (SAMPL) 9 challenge, we applied the Poisson-Boltzmann (PB) surface area (SA) approach to predict the toluene/water transfer free energy and partition coefficient (log Ptoluene/water) from SFEs. For each solute, only a single conformation automatically generated by the free software Open Babel was used. The PB calculation directly adopts our previously optimized boundary definition - a set of general AMBER force field 2 (GAFF2) atom-type based sphere radii for solute atoms. For the non-polar SA model, we newly developed the solvent-related molecular surface tension parameters γ and offset b for toluene and cyclohexane targeting experimental SFEs. This approach yielded the highest predictive accuracy in terms of root mean square error (RMSE) of 1.52 kcal mol-1 in transfer free energy for 16 small drug molecules among all 18 submissions in the SAMPL9 blind prediction challenge. The re-evaluation of the challenge set using multi-conformation strategies based on molecular dynamics (MD) simulations further reduces the prediction RMSE to 1.33 kcal mol-1. At the same time, an additional evaluation of our PBSA method on the SAMPL5 cyclohexane/water distribution coefficient (log Dcyclohexane/water) prediction revealed that our model outperformed COSMO-RS, the best submission model with RMSEPBSA = 1.88 versus RMSECOSMO-RS = 2.11 log units. Two external log Ptoluene/water and log Pcyclohexane/water datasets that contain 110 and 87 data points, respectively, are collected for extra validation and provide an in-depth insight into the error source of the PBSA method.

Solvent quality and nonbiological oligomer folding: revisiting conventional paradigms.

We report on extensive molecular dynamics atomistic simulations of a meta-substituted poly-phenylacetylene (pPA) foldamer dispersed in three solvents, water H2O, cyclohexane cC6H12, and n-hexane nC6H14, and for three oligomer lengths 12mer, 16mer and 20mer. At room temperature, we find a tendency of the pPA foldamer to collapse into a helical structure in all three solvents but with rather different stability character, stable in water, marginally stable in n-hexane, unstable in cyclohexane. In the case of water, the initial and final number of hydrogen bonds of the foldamer with water molecules is found to be unchanged, with no formation of intrachain hydrogen bonding, thus indicating that hydrogen bonding plays no role in the folding process. In all three solvents, the folding is found to be mainly driven by electrostatics, nearly identical in the three cases, and largely dominant compared to van der Waals interactions that are different in the three cases. This scenario is also supported by the analysis of distribution of the bond and dihedral angles and by a direct calculation of the solvation and transfer free energies via thermodynamic integration. The different stability in the case of cyclohexane and n-hexane notwithstanding their rather similar chemical composition can be traced back to the different entropy-enthalpy compensation that is found similar for water and n-hexane, and very different for cyclohexane. A comparison with the same properties for poly-phenylalanine oligomers underscores the crucial differences between pPA and peptides. To highlight how these findings can hardly be interpreted in terms of a simple "good" and "poor" solvent picture, a molecular dynamics study of a bead-spring polymer chain in a Lennard-Jones fluid is also included.

Insight into the K channel's selectivity from binding of K+, Na+ and water to N-methylacetamide.

In potassium channels that conduct K+ selectively over Na+, which sites are occupied by K+ or water and the mechanism of selectivity are unresolved questions. The combination of the energetics and the constraints imposed by the protein structure yield the selective permeation and occupancy. To gain insight into the combination of structure and energetics, we performed density functional theory (DFT) calculations of multiple N-methyl acetamide (NMA) ligands binding to K+ and Na+, relative to hydrated K+ and Na+. NMA is an analogue of the amino acid backbone and provides the carbonyl binding to the ions that occurs in most binding sites of the K+ channel. Unconstrained optimal structures are obtained through geometry optimization calculations of the NMA ligand binding. The complexes formed by 8 NMA binding to the cations have the O atoms positioned in nearly identical locations as the O atoms in the selectivity filter. The transfer free energies between bulk water and K+ or Na+ bound to 8 NMA are almost identical, implying there is no selectivity by a single site. For water optimized with 8 NMA, binding is weak and O atoms are not positioned as in the K+ channel selectivity filter, suggesting that the ions are much more favored than water. Optimal structures of 8 NMA binding with two cations (K+ or Na+) are stable and have lower binding free energy than the optimal structures with just one cation. However, in the Na+ case, the optimal structure deforms and does not match the K+ channel; that is, two bound Na+ are destabilizing. In contrast, the two K+ structure is stabilized and the selectivity free energy favors K+. Overall, this study shows that binding site occupancy and the mechanism for K+ selectivity involves multiple K+ binding in multiple neighboring layers or sites of the K+ channel selectivity filter.

Prediction of toluene/water partition coefficients of SAMPL9 compounds: comparison of the molecular dynamics force fields GAFF/RESP and GAFF/IPolQ-Mod + LJ-fit.

The SAMPL9 blind challenge aims to predict the toluene/water partition coefficient of 16 active pharmaceutical ingredients. In this work, the transfer free energy between the solvation in water and toluene is predicted by molecular dynamics simulations using the MBAR method [M. R. Shirts and J. D. Chodera, J. Chem. Phys., 2008, 129, 123105] with replica exchange molecular dynamics [Y. Sugita, A. Kitao and Y. Okamoto, J. Chem. Phys., 2000, 113, 6042-6051]. Thereby, simulation results using the force field GAFF/IPolQ-Mod + LJ-fit [A. Mecklenfeld and G. Raabe, ADMET and DMPK, 2020, 8, 274-296] are compared to simulations with the standard GAFF/RESP model [J. Wang, R. M. Wolf, J. W. Caldwell, P. A. Kollman and D. A. Case, J. Comput. Chem., 2004, 25, 1157-1174]. By statistical evaluation of RMSD and R2, we compare the results with other participants of the blind challenge. Furthermore, we provide a detailed analysis of solvation structures using the combined distribution function for simulations in water and the plane projection analysis for simulations in toluene, and we work out differences and similarities of the two force fields. These studies allow to gain important insights to increase the understanding of the mechanism of interactions between the drugs and the solvent.

PSPICA Force Field Extended for Proteins and Peptides.

Many coarse-grained (CG) molecular dynamics (MD) studies have been performed to investigate biological processes involving proteins and lipids. CG force fields (FFs) in these MD studies often use implicit or nonpolar water models to reduce computational costs. CG-MD using water models cannot properly describe electrostatic screening effects owing to the hydration of ionic segments and thus cannot appropriately describe molecular events involving water channels and pores through lipid membranes. To overcome this issue, we developed a protein model in the pSPICA FF, in which a polar CG water model showing the proper dielectric response was adopted. The developed CG model greatly improved the transfer free energy profiles of charged side chain analogues across the lipid membrane. Application studies on melittin-induced membrane pores and mechanosensitive channels in lipid membranes demonstrated that CG-MDs using the pSPICA FF correctly reproduced the structure and stability of the pores and channels. Furthermore, the adsorption behavior of the highly charged nona-arginine peptides on lipid membranes changed with salt concentration, indicating the pSPICA FF is also useful for simulating protein adsorption on membrane surfaces.

Prediction of binary mutual solubility via liquid-liquid interfacial tension

The solubility property is of interest to chemical, physical, pharmaceutical, material and environmental sciences. It is a fascinating task to understand the intrinsic reason underlying the solubility behavior. The theoretical relation between binary mutual solubility and liquid-liquid interfacial tension was derived, in which the partitioning of solute molecules between two coexisting liquid phases is determined by the transfer free energy per unit segment for a chain-like solute molecule expressed in terms of solute-solvent interfacial tension. This general theory of solubility is in good accord with experiment for binary mutual solubility and molar transfer free energy of solute molecules.