Free Energy Of Transfer Research Articles

Deciphering Ethanol-Driven Swelling, Rupturing, Aggregation, and Fusion of Lipid Vesicles Using Coarse-Grained Molecular Dynamics Simulations.

Traditionally, liquid ethanol is known to enhance the permeability of lipid membranes and causes vesicle aggregation and fusion. However, how the amphiphilic ethanol molecules perturb the lipid vesicles to facilitate their aggregation or fusion has not been addressed at any level of molecular simulations. Herein, not only have we developed a coarse-grained (CG) model for liquid ethanol, its aqueous mixture, and hydrated lipid membranes for molecular dynamics (MD) simulations, but also utilized it to delineate the aggregation and fusion of lipid vesicles using CG-MD simulations with multimillion particles. We have systematically parametrized the force-field for pure ethanol and its interactions with hydrated POPC and POPE model lipid membranes. In this process, we have successfully reproduced the bulk ethanol structure and concentration-dependent density of aqueous ethanol. To quantify the interaction of ethanol with lipid membranes, we have reproduced the transfer free energy of the ethanol molecule across the hydrated bilayers, and the concentration-dependent distribution of ethanol molecules across the lipid bilayers. After having acceptable force-field parameters for ethanol-membrane interactions, we have checked the effect of ethanol toward the vesicles comprising POPC lipids. We observe a rapid increase in the size of the POPC lipid vesicles with increasing amounts of ethanol up to 30 mol %. We unambiguously observe swelling and decrease in the thickness of the POPC vesicles with increasing amounts of ethanol up to 30 mol %, beyond which the vesicles begin to lose their integrity and rupture at higher mol % of ethanol. The fusion study of two vesicles demonstrates that fused vesicles can be obtained from 20 to 30 mol % of ethanol provided that they are brought closer than a critical distance at a particular mol %. The multivesicle simulations show that along with the increase in the sizes of vesicles the propensity of vesicle aggregation increases as the mol % of ethanol increases.

Molecular descriptors suggest stapling as a strategy for optimizing membrane permeability of cyclic peptides.

Cyclic peptides represent a promising class of drug candidates. A significant obstacle limiting their development as therapeutics is the lack of an ability to predict their membrane permeability. We use molecular dynamics simulations to assess the ability of a set of widely used parameters in describing the membrane permeability of a set of model cyclic peptides; the parameters include polar surface area (PSA), the number of hydrogen bonds, and transfer free energy between an aqueous phase and a membrane mimicking phase. These parameters were found to generally correlate with the membrane permeability of the set of cyclic peptides. We propose two new descriptors, the charge reweighted PSA and the non-polar surface area to PSA ratio; both show enhanced correlation with membrane permeability. This inspired us to explore crosslinking of the peptide to reduce the accessible surface area of the backbone polar atoms, and we find that this can indeed result in reductions in the accessible PSA. This gives reason to speculate that crosslinking may result in increased permeability, thus suggesting a new scaffold for the development of cyclic peptides as potential therapeutics.

Oxidation of iminodiethanol by Ce (IV) in microheterogeneous system: a comprehensive kinetic analysis

A comprehensive kinetic analysis of catalyzed oxidative degradation of iminodiethanol by Ce(IV) in pure aqueous and microheterogeneous or surfactant media has been reported. The oxidation reactions were first order with respect to [Ce (IV)], the dependence of rate on iminodiethanol concentration is first order, the rate constant values increased with increasing dielectric constant of the medium and the entropy of activation was negative. Kinetic information suggested that the oxidation reactions proceed through intermediate complex formation. The profile of pseudo-first order rate constant, kψ against [SDS] (sodium dodecyl sulfate) shows a maximum at about the concentration near which the randomized surfactant monomers started aggregating for the formation of micelle. To demonstrate the kinetic pattern and to evaluate the micelle-reactant binding constant values, Berezin’s model has been advanced. The transfer free energy per mole of the solute from water to the micellar phase has also been computed. Activation parameters for the oxidation reaction are obtained from the temperature dependence studies. Basing on all analytical results plausible mechanisms are proposed for the catalyzed oxidation of iminodiethanol by Ce (IV) both in aqueous and surfactant medium.

Cucurbiturils mimicked by low polarizability solvents with pre-formed cavities: an empirical model to predict hydrocarbon selectivity.

Relative binding affinities of a series of nine rigid hydrocarbons towards the cavity formed by a portion of the inner wall of cucurbit[8]uril (CB[8]) and a positive auxiliary guest were determined by competitive 19F NMR titrations in deuterium oxide. The corresponding free binding energies were corrected by the hydrocarbon computed solvation energies to obtain their free energies of transfer from the gas phase to the CB[8]/auxiliary guest cavity. These energies correlate linearly with the hydrocarbon static polarizabilities, thereby suggesting that the selectivity is driven, perhaps exclusively, by dispersive interactions between the hydrocarbons and the tailor-made cavity, regardless of the degree of unsaturation of the guests. The free energies of transfer also correlate linearly with the energy released upon introduction of the hydrocarbon into a pre-formed cavity extruded from a solvent (benzene) selected to mimic the polarity and polarizability of the CB[8]/auxiliary probe cavity – and this, with a unity slope. Among other features, this empirical model also accurately predicts the relative binding affinities of various rigid hydrocarbons to CB[6] and CB[7], as well as noble gases to CB[5], when the macrocycles are mimicked with pre-formed cavities in perfluorohexane or perfluorohexane/benzene mixtures, both being notoriously non-polar and non-polarizable environments.

Quantifying Protein Electrostatic Interactions in Cells by Nuclear Magnetic Resonance Spectroscopy.

Most proteins perform their functions in cells. How the cellular environment modulates protein interactions is an important question. In this work, electrostatic interactions between protein charges were studied using in-cell nuclear magnetic resonance (NMR) spectroscopy. A total of eight charge pairs were introduced in protein GB3. Compared to the charge pair electrostatic interactions in a buffer, five charge pairs in cells displayed no apparent changes whereas three pairs had the interactions weakened by more than 70%. Further investigation suggests that the transfer free energy is responsible for the electrostatic interaction modulation. Both the transfer free energy of the folded state and that of the unfolded state can contribute to the cellular environmental effect on protein electrostatics, although the latter is generally larger (more negative) than the former. Our work highlights the importance of direct in-cell studies of protein interactions and thus protein function.

Designing Catalytic Systems Using Binary Solvent Mixtures: Impact of Mole Fraction of Water on Hydride Transfer.

The free energy for hydride transfer reactions of transition metal hydrides is known to be influenced by solvent effects. The first-row transition metal hydride [HNi(dmpe)2][BF4] (dmpe = 1,2-bis(dimethylphosphino)ethane) has starkly different hydride transfer reactivities with CO2 in different solvents. A binary mixture of water and acetonitrile was used to tune the hydride transfer reactivity of HNi(dmpe)2+ with CO2 so that the free energy for this reaction approached zero. Various mole fractions of water were tested and a linear relationship between the hydride transfer free energy and solvent composition was established for 0-0.24 mole fraction of water. A deviation from linearity was found upon moving toward higher mole fractions of water. The tuning of the free energy for hydride transfer allowed HNi(dmpe)2+ to be used as a catalyst for the hydrogenation of CO2. The optimized catalyst conditions produced 58 turnovers at room temperature in 0.082 mole fraction of water using 60 atm of a 1:1 mixture of H2 to CO2 gas.

Modeling lipid-protein interactions for coarse-grained lipid and Cα protein models.

Biological membranes that play major roles in diverse functions are composed of numerous lipids and proteins, making them an important target for coarse-grained (CG) molecular dynamics (MD) simulations. Recently, we have developed the CG implicit solvent lipid force field (iSoLF) that has a resolution compatible with the widely used Cα protein representation [D. Ugarte La Torre and S. Takada, J. Chem. Phys. 153, 205101 (2020)]. In this study, we extended it and developed a lipid-protein interaction model that allows the combination of the iSoLF and the Cα protein force field, AICG2+. The hydrophobic-hydrophilic interaction is modeled as a modified Lennard-Jones potential in which parameters were tuned partly to reproduce the experimental transfer free energy and partly based on the free energy profile normal to the membrane surface from previous all-atom MD simulations. Then, the obtained lipid-protein interaction is tested for the configuration and placement of transmembrane proteins, water-soluble proteins, and peripheral proteins, showing good agreement with prior knowledge. The interaction is generally applicable and is implemented in the publicly available software, CafeMol.

Electronic coupling induced by structural deformation and magnetic dopants in dual-metal Janus MoReS3 and WReS3 for hydrogen evolution reaction

The layered MoReS3 and WReS3 were proposed for investigation into the synergistic effect between structural deformation and dopants on regulating hydrogen evolution reaction (HER) activity. The Magnetic dopants give rise to an electronic structure with spin polarization characteristic due to strong electron–electron interactions while the Gibbs free energy, work function and charge transfer are strongly dependent on structural deformation. This work provides a new insight into regulating catalyst’s electronic structure and reactive activity in Janus atomic configuration.

The Influence of Single-Atom Fe2+/3+N4 Spin State on the Electroreduction of CO2 to CO/HCOOH by Analyzing Proton/Electron Transfer Mechanisms and Free Energy Evolutions

The Influence of Single-Atom Fe^2+/3+N₄ Spin State on the Electroreduction of CO₂ to CO/HCOOH by Analyzing Proton/Electron Transfer Mechanisms and Free Energy Evolutions

Microemulsion as Model to Predict Free Energy of Transfer of Electrolyte in Solvent Extraction

ABSTRACT We consider here the extraction of metals in the form of salts transferred from an aqueous to a solvent phase. Extraction is triggered by complexation and quenched by the associated necessary reorganization of the structured solvent phase. The extraction of ions changes the relative fraction of extractant molecules that is not part of the highly curved surfactant monolayer and is dispersed molecularly in the oil, and also the polar volume fraction including co-extracted water. The free energy and corresponding microstructures of the water-poor microemulsions are modelled in the frame of the Gaussian random fields (GRF) model. The curvature frustration energy significantly contributes to the free energy of extraction. A typical example of predicted isotherm using the GRF model is compared to the classically considered supramolecular complex formation, together with a minimal Langmuir model and an explicit monomer-to-film equilibrium of amphiphilic extractant. The corresponding small-angle scattering spectra and morphology changes are shown. One implication is that selectivity between a hydrated and a non-hydrated species is concentration dependent and cannot be considered as a constant as a function of the extractant concentration.

Pressure Unfolding of Proteins: New Insights into the Role of Bound Water.

High pressures can be detrimental for protein stability, resulting in unfolding and loss of function. This phenomenon occurs because the unfolding transition is accompanied by a decrease in volume, which is typically attributed to the elimination of cavities that are present within the native state as a result of packing defects. We present a novel computational approach that enables the study of pressure unfolding in atomistically detailed protein models in implicit solvent. We include the effect of pressure using a transfer free energy term that allows us to decouple the effect of protein residues and bound water molecules on the volume change upon unfolding. We discuss molecular dynamics simulations results using this protocol for two model proteins, Trp-cage and staphylococcal nuclease (SNase). We find that the volume reduction of bound water is the key energetic term that drives protein denaturation under the effect of pressure, for both Trp-cage and SNase. However, we note differences in unfolding mechanisms between the smaller Trp-cage and the larger SNase protein. Indeed, the unfolding of SNase, but not Trp-cage, is seen to be further accompanied by a reduction in the volume of internal cavities. Our results indicate that, for small peptides, like Trp-cage, pressure denaturation is driven by the increase in solvent accessibility upon unfolding, and the subsequent increase in the number of bound water molecules. For larger proteins, like SNase, the cavities within the native fold act as weak spots, determining the overall resistance to pressure denaturation. Our simulations display a striking agreement with the pressure-unfolding profile experimentally obtained for SNase and represent a promising approach for a computationally efficient and accurate exploration of pressure-induced denaturation of proteins.

SAMPL7 blind challenge: quantum-mechanical prediction of partition coefficients and acid dissociation constants for small drug-like molecules.

The physicochemical properties of a drug molecule determine the therapeutic effectiveness of the drug. Thus, the development of fast and accurate theoretical approaches for the prediction of such properties is inevitable. The participation to the SAMPL7 challenge is based on the estimation of logP coefficients and pKa values of small drug-like sulfonamide derivatives. Thereby, quantum mechanical calculations were carried out in order to calculate the free energy of solvation and the transfer energy of 22 drug-like compounds in different environments (water and n-octanol) by employing the SMD solvation model. For logP calculations, we studied eleven different methodologies to calculate the transfer free energies, the lowest RMSE value was obtained for the M06L/def2-TZVP//M06L/def2-SVP level of theory. On the other hand, we employed an isodesmic reaction scheme within the macro pKa framework; this was based on selecting reference molecules similar to the SAMPL7 challenge molecules. Consequently, highly well correlated pKa values were obtained with the M062X/6-311+G(2df,2p)//M052X/6-31+G(d,p) level of theory.

Protein Cold Denaturation in Implicit Solvent Simulations: A Transfer Free Energy Approach.

Proteins are stable over a narrow temperature range, with hot and cold denaturation occurring outside of this window, both of which adversely affect protein function. While hot unfolding is entropically driven, cold denaturation, on the other hand, results from a more favorable free energy associated with the interaction of water with apolar groups at low temperature. Because of the key role of water in this latter process, capturing cold denaturation using implicit solvent models is challenging. We propose here a novel computational approach to develop an implicit solvent model that accounts for both hot and cold denaturation in simulations involving atomistically detailed protein representations. By mining a large number of protein structures solved by nuclear magnetic resonance, we derive transfer free energy contributions for the backbone and amino acids side chains representing the transfer of these moieties between water at two different temperatures. Using Trp-cage as a model system, we show that the implicit solvent model constructed using these temperature-dependent free energies of transfer recovers the parabolic temperature dependence of protein stability, capturing both hot and cold denaturation. The resulting cold-unfolded conformations show reduced secondary structure content but preserve most of their internal hydrogen-bonding network, in contrast to the extended configurations with no hydrogen-bonding populated during heat-induced denaturation.

Translation of Chemical Structure into Dissipative Particle Dynamics Parameters for Simulation of Surfactant Self-Assembly.

Dissipative particle dynamics (DPD) can be used to simulate the self-assembly properties of surfactants in aqueous solutions, but in order to simulate a new compound, a large number of new parameters are required. New methods for the calculation of reliable DPD parameters directly from chemical structure are described, allowing the DPD approach to be applied to a much wider range of organic compounds. The parameters required to describe the bonded interactions between DPD beads were calculated from molecular mechanics structures. The parameters required to describe the nonbonded interactions were calculated from surface site interaction point (SSIP) descriptions of molecular fragments that represent individual beads. The SSIPs were obtained from molecular electrostatic potential surfaces calculated using density functional theory and used in the SSIMPLE algorithm to calculate transfer free energies between different bead liquids. This approach was used to calculate DPD parameters for a range of different types of surfactants, which include ester, amide, and sugar moieties. The parameters were used to simulate the self-assembly properties in aqueous solutions, and comparison of the results for 27 surfactants with the available experimental data shows that these DPD simulations accurately predict critical micelle concentrations, aggregation numbers, and the shapes of the supramolecular assemblies formed. The methods described here provide a general approach to determining DPD parameters for neutral organic compounds of arbitrary structure.

How acidity rules synergism and antagonism in liquid–liquid extraction by lipophilic extractants—Part II: application of the ienaic modelling

ABSTRACT In this article Part II, we consider the application of ienaic modeling for solvent extraction of rare earths in the case of the mixed DMDOHEMA/HDEHP extractant system. The system exhibits a synergistic extraction effect depending on the acid concentration and the extractant mole fraction, as demonstrated in the experimental article Part I. In this work, we directly compare experimental findings with theoretical predictions of the droplet model. The model considers the effective free energy of transfer as a combination of competing molecular forces, but contrary to previous micelle models that focus only on the dominant stoichiometry, it allows calculations of free energies of every possible spherical aggregate. The resulting image of the extraction process is that different behaviors can be obtained depending on the acidity and mole fraction of extractants, which are associated with different aggregation regimes in a complex free energy landscape of the system. Nevertheless, self-assembly is tuned by the extraction of all solutes, and not only the target metal cations.

The Roots of Genetic Coding in Aminoacyl-tRNA Synthetase Duality.

Codon-dependent translation underlies genetics and phylogenetic inferences, but its origins pose two challenges. Prevailing narratives cannot account for the fact that aminoacyl-tRNA synthetases (aaRSs), which translate the genetic code, must collectively enforce the rules used to assemble themselves. Nor can they explain how specific assignments arose from rudimentary differentiation between ancestral aaRSs and corresponding transfer RNAs (tRNAs). Experimental deconstruction of the two aaRS superfamilies created new experimental tools with which to analyze the emergence of the code. Amino acid and tRNA substrate recognition are linked to phase transfer free energies of amino acids and arise largely from aaRS class-specific differences in secondary structure. Sensitivity to protein folding rules endowed ancestral aaRS-tRNA pairs with the feedback necessary to rapidly compare alternative genetic codes and coding sequences. These and other experimental data suggest that the aaRS bidirectional genetic ancestry stabilized the differentiation and interdependence required to initiate and elaborate the genetic coding table.

How Acidity Rules Synergism and Antagonism in Liquid–Liquid Extraction by Lipophilic Extractants—Part I: Determination of Nanostructures and Free Energies of Transfer

ABSTRACT Efficient formulations used in hydrometallurgy are often based on synergistic action of two oil-soluble extractants at an optimized mole fraction. In this series of two papers, we describe the N,N’-dimethyl-N,N’-dioctylhexylethoxymalonamide (DMDOHEMA)/di(2-ethylexyl) phosphoric acid (HDEHP) system, and how expression of the synergistic effect varies with acidity, using the three common representations: distribution ratios, yields, and free energies of transfer. The experimental results are detailed in this first part (Part I) with the so-called supramolecular approach, which considers the reverse micelle-like aggregates formed by the lipophilic extractant molecules. It shows that no specific aggregation state is observed at the maximum of synergism and antagonism. Besides, the critical aggregation concentration that characterizes the micellization free energy appears to follow some synergistic trends but cannot explain how acid tunes synergism to antagonism of this mixed system. Based on these results, Part II proposes a theoretical model based on the ienaic approach to interpret acid effect on synergism and antagonism.

Proton transfer free energy and enthalpy from water to methanol

Proton transfer free energies and proton transfer enthalpies at the interface of different solvents are very important in chemistry and biology. In the present work, we present a general model to describe theoretically the proton transfer at the interface of two given solvents. The model is simple to apply, affordable and stable. It is based on first principles calculations of neutral and protonated clusters of the solvent molecules. The model is described and applied to the calculation of the water-methanol proton transfer free energy and enthalpy at standard conditions. We have thoroughly explored the potential energy surfaces (PESs) of neutral and protonated water clusters as well as neutral and protonated methanol clusters in the solvent phase. The located structures have been optimized at the MN15/6-31++G(d,p) level of theory. Using the favourable structures and the proposed model, the water-methanol proton transfer free energy and enthalpy are evaluated to be −6.1 kJ mol−1 and −13.3 kJ mol−1, respectively. The calculated water-methanol proton transfer enthalpy is found to be in excellent agreement with the experimental estimate of −15.9 kJ mol−1, based on the tetraphenylarsonium-tetraphenylborate (TATB) approach.

Transfer free energy of micro-hydrated ion clusters from water into acetonitrile solvent

The transfer free energies of micro-hydrated alkali ions (Li+, Na+, K+, and Cs+) and halide ions (F-, Cl-, Br-, and I-) clusters from bulk water to bulk acetonitrile are investigated within the framework of reaction density functional theory (RxDFT), in which the formation of micro-hydrated ion clusters containing one to four water molecules is treated as associated reaction. By analyzing the free energy of hydration and solvation, we show that the micro-hydrated ion clusters, [M(H2O)n]+, exist stably in both water and acetonitrile and a larger percentage of the total electrostatic interactions of ions is contributed by their first solvation shell water molecules. For the transfer free energy of bare ions, the calculated results agree well with the values of experimental observation. The transfer free energy significantly decreases as the size of bare ions and the number of water molecules in the cluster increase. This dependence is stronger for small ions than for large ions. Moreover, the lowest transfer free energy is correspond to the different coordinated number of water molecule (Nw). For Li+, Na+, F-, Cl-, Br-, and I- ion, the lowest transfer free energy are correspond to Nw = 4, while for K+ and Cs+ ion, Nw with the lowest transfer free energy are 3 and 2, respectively. Our findings provide not only the framework to predict transfer free energy but also theoretical guidance for solvent extraction, ion-selective electrodes, biological ion channels, and phase transfer catalysis.

The solubility of N-acetyl amino acid amides in organic acid and alcohol solutions: Mechanistic insight into structural protein solubilization

Structural proteins such as spider silk and silkworm silk are generally poorly soluble in aqueous and organic solutions, making them difficult to manipulate in manufacturing processes. Although some organic acids and alcohols, such as formic acid and hexafluoroisopropanol (HFIP), effectively solubilize poorly soluble proteins, little is known about their protein solubilization mechanism. In this study, the solubility of N-acetyl amino acid amide compounds in organic solvents—formic acid, acetic acid, HFIP and isopropanol—was measured to clarify the protein solubilization mechanism at the amino acid residue level. On the basis of thermodynamic analyses of the solubility in terms of the transfer free energy (from water to organic solvents), every organic solvent was found to be effective in thermodynamically stabilizing hydrophobic amino acid side chains in the liquid phase. Formic acid and HFIP were comparably effective in the stabilization of the polypeptide backbone, whereas acetic acid and isopropanol were ineffective. Therefore, the significant solubilizing effect of formic acid and HFIP on the structural proteins was attributed to their favorable interactions with hydrophobic amino acid side chains and with the polypeptide backbone of the proteins. The present findings are useful for the optimization of protein manipulation and amino acid sequence design.