Energies Of Solvation In Water Research Articles

Solvation Thermodynamics of Solutes in Water and Ionic Liquids Using the Multiscale Solvation-Layer Interface Condition Continuum Model.

Molecular assembly processes are generally driven by thermodynamic properties in solutions. Atomistic modeling can be very helpful in designing and understanding complex systems, except that bulk solvent is very inefficient to treat explicitly as discrete molecules. In this work, we develop and assess two multiscale solvation models for computing solvation thermodynamic properties. The new SLIC/CDC model combines continuum solvent electrostatics based on the solvent layer interface condition (SLIC) with new statistical thermodynamic models for hydrogen bonding and nonpolar modes: cavity formation, dispersion interactions, combinatorial mixing (CDC). Given the structures of 500 solutes, the SLIC/CDC model predicts Gibbs energies of solvation in water with an average accuracy better than 1 kcal/mol, when compared to experimental measurements, and better than 0.8 kcal/mol, when compared to explicit-solvent molecular dynamics simulations. The individual SLIC/CDC energy mode values agree quantitatively with those computed from explicit-solvent molecular dynamics. The previously published SLIC/SASA multiscale model combines the SLIC continuum electrostatic model with the solvent-accessible surface area (SASA) nonpolar energy mode. With our new, improved parametrization method, the SLIC/SASA model now predicts Gibbs energies of solvation with better than 1.4 kcal/mol average accuracy in aqueous systems, compared to experimental and explicit-solvent molecular dynamics, and better than 1.6 kcal/mol average accuracy in ionic liquids, compared to explicit-solvent molecular dynamics. Both models predict solvation entropies, and are the first implicit-solvation models capable of predicting solvation heat capacities.

Reparametrisation of united-atom amine solvation in the GROMOS force field

ABSTRACTNew parameters for ammonia, mono-, di- and trimethylated amine compatible with GROMOS force fields are presented. A directed search in parameter space by steepest descent minimisation led to an optimised charge set with good agreement to experimental data on absolute and relative free energies of solvation in water, chloroform and carbon tetrachloride. The final model is characterised in terms of structural and dynamic properties.

Calculation of distribution coefficients in the SAMPL5 challenge from atomic solvation parameters and surface areas.

In the context of SAMPL5, we submitted blind predictions of the cyclohexane/water distribution coefficient (D) for a series of 53 drug-like molecules. Our method is purely empirical and based on the additive contribution of each solute atom to the free energy of solvation in water and in cyclohexane. The contribution of each atom depends on the atom type and on the exposed surface area. Comparatively to similar methods in the literature, we used a very small set of atomic parameters: only 10 for solvation in water and 1 for solvation in cyclohexane. As a result, the method is protected from overfitting and the error in the blind predictions could be reasonably estimated. Moreover, this approach is fast: it takes only 0.5s to predict the distribution coefficient for all 53 SAMPL5 compounds, allowing its application in virtual screening campaigns. The performance of our approach (submission 49) is modest but satisfactory in view of its efficiency: the root mean square error (RMSE) was 3.3 log D units for the 53 compounds, while the RMSE of the best performing method (using COSMO-RS) was 2.1 (submission 16). Our method is implemented as a Python script available at https://github.com/diogomart/SAMPL5-DC-surface-empirical .

Cytisine basicity, solvation, log P, and log D theoretical determination as tool for bioavailability prediction

Cytisine, an α4β2 nicotinic receptor partial agonist, is a plant alkaloid widely used as a smoking cessation agent. Despite long history of use, knowledge on pharmacokinetics of cytisine still demands an extension. This work is aimed at theoretical determination of physicochemical parameters that affect the bioavailability of cytisine. The acidic dissociation constant, Gibbs free energy of solvation in water and n-octanol as well as n-octanol/water partition coefficient and n-octanol/water distribution coefficient of cytisine were calculated as quantities corresponding to its solubility and permeability. Cytisine structure was optimized with several quantum chemical methods—ab initio: HF and MP2, and DFT functionals (B3LYP, B3LYP-D3, CAM-B3LYP, M06-2X, TPSS, VSXC) with 6-311++G(d,p) basis set. Solvation of cytisine in water and n-octanol was determined with the SMD continuum model. It was shown that lipophilicity of cytisine depends on the pH of an environment. Protonated cytisine, the most populated state under acidic conditions, is characterized by enhanced hydrophilicity. Then neutral cytisine, dominating in a basic environment, demonstrates more lipophilic character. It appears that cytisine is very well soluble in the gastrointestinal (GI) tract fluids. Then the distribution of cytisine ought to occur very rapidly. However, permeability of cytisine through the mucous membrane of the GI tract may be limited, leading to the diminished bioavailability.

Bio-Inspired Electroactive Organic Molecules for Aqueous Redox Flow Batteries. 1. Thiophenoquinones

Redox flow batteries (RFB) utilizing water-soluble organic redox couples are a new strategy for low-cost, eco-friendly, and durable stationary electrical energy storage. Previous studies have focused on benzoquinones, napthoquinones, and anthraquinones as the electroactive species. Here, we explore a new class of molecules—thiophenoquinones—specifically focusing on the caldariellaquinone-, sulfolobusquinone-, and benzodithiophenoquinone-like frameworks that are used for metabolic processes in thermophilic aerobic Sulfolobus archaebacteria. We demonstrated that B3LYP/6-311+G(d,p) thermochemical calculations (using the SMD solvation model) reproduce experimental reduction potentials to within ±0.04 V. We then studied the effect of amine, hydroxyl, methyl, fluoro, phosphonic acid, sulfonic acid, carboxylic acid, and nitro functional group modifications on the reduction potential and Gibbs energy of solvation in water (using density functional theory) and aqueous solubility (using cheminformatics). Next we enumerated all of the 10 611 possible combinations of functional group substitutions on these frameworks and identified 1056 potential molecules with solubilities exceeding 2 mol/L; of these, 36 molecules have reduction potentials below 0.25 V and 15 molecules above 0.95 V (versus the standard hydrogen electrode (SHE)). The combination of high solubility and wide voltage range makes these molecules promising candidates for high performance aqueous RFB applications. Finally, using our data set of ab initio reduction potentials, we developed a cheminformatics model that predicts ab initio reduction potentials to within ±0.09 V based solely on molecular connectivity. We found that a model trained with as few as 200 examples generates rank-ordered predictions allowed us to identify the highest performance candidates with half the number of ab initio calculations. This offers a strategy for improving the tractability of future computational searches for high performance RFB molecules.

Liquid–Liquid Extraction of Uranyl by TBP: The TBP and Ions Models and Related Interfacial Features Revisited by MD and PMF Simulations

We report a molecular dynamics (MD) study of biphasic systems involved in the liquid-liquid extraction of uranyl nitrate by tri-n-butylphosphate (TBP) to hexane, from "pH neutral" or acidic (3 M nitric acid) aqueous solutions, to assess the model dependence of the surface activity and partitioning of TBP alone, of its UO2(NO3)2(TBP)2 complex, and of UO2(NO3)2 or UO2(2+) uncomplexed. For this purpose, we first compare several electrostatic representations of TBP with regards to its polarity and conformational properties, its interactions with H2O, HNO3, and UO2(NO3)2 species, its relative free energies of solvation in water or oil environments, the properties of the pure TBP liquid and of the pure-TBP/water interface. The free energies of transfer of TBP, UO2(NO3)2, UO2(2+), and the UO2(NO3)2(TBP)2 complex across the water/oil interface are then investigated by potential of mean force (PMF) calculations, comparing different TBP models and two charge models of uranyl nitrate. Describing uranyl and nitrate ions with integer charges (+2 and -1, respectively) is shown to exaggerate the hydrophilicity and surface activity of the UO2(NO3)2(TBP)2 complex. With more appropriate ESP charges, mimicking charge transfer and polarization effects in the UO2(NO3)2 moiety or in the whole complex, the latter is no more surface active. This feature is confirmed by MD, PMF, and mixing-demixing simulations with or without polarization. Furthermore, with ESP charges, pulling the UO2(NO3)2 species to the TBP phase affords the formation of UO2(NO3)2(TBP)2 at the interface, followed by its energetically favorable extraction. The neutral complexes should therefore not accumulate at the interface during the extraction process, but diffuse to the oil phase. A similar feature is found for an UO2(NO3)2(Amide)2 neutral complex with fatty amide extracting ligands, calling for further simulations and experimental studies (e.g., time evolution of the nonlinear spectroscopic signature and of surface tension) on the interfacial landscape upon ion extraction.

Amphiphilic Drug-Like Molecules Accumulate in a Membrane below the Head Group Region

The partitioning behavior of drug-like molecules into biomembranes has a crucial impact on the design and efficacy of therapeutic drugs. Thermodynamic properties connected with the interaction of molecules with membranes can be evaluated by calculating free-energy profiles normal to the membrane surface. We calculated the free-energy profiles of 25 drug-like molecules in a 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) membrane and free energies of solvation in water and heptane using two methods, molecular dynamics (MD) simulations with the Berger lipid force field and COSMOmic, based on a continuum conductor-like screening model for realistic solvation (COSMO-RS). The biased MD simulations (in total ∼22 μs long) were relatively computationally expensive, whereas the COSMOmic approach offered a significantly less expensive alternative. Both methods provided similar results and showed that the studied amphiphilic drug-like molecules accumulate in the membrane, with the majority localized below the head group region. The MD simulations were more lipophilic and gave free-energy profiles that were systematically deeper than those calculated by COSMOmic. To investigate the physical nature of the increased lipophilicity, we analyzed a water/heptane system and identified that it is most likely caused by overestimation of the attractive term of the Lennard-Jones potential in lipid tails. We concluded that COSMOmic can be successfully used for high-throughput computations of global thermodynamic properties, for example, partition coefficients and energy barrier heights, in phosphocholine membranes. In contrast, MD is better for investigating local properties like molecular positioning and orientation in the membrane because they more accurately reflect the complex structure of lipid bilayers. MD is also useful for studies of highly complex systems, for example, drug-membrane-protein interactions.

Density Functional Theoretical Study on the Reduction Potentials of Catechols in Water

= , (2)where F is the Faraday constant and the factor of 2 signifiesa two electron process.The standard free energy of each species (BQ and CAT) inan aqueous solution, , can be expressed as the sum ofthe gas-phase standard free energy, , and the standardfree energy of solvation in water, :.(3)The standard free energy of each species in the gas phase, , was obtained using the following equation:.(4)The total energy of the molecule at 0 K ( E

Membrane Protein Simulations Using AMBER Force Field and Berger Lipid Parameters.

AMBER force fields are among the most commonly used in molecular dynamics (MD) simulations of proteins. Unfortunately, they lack a specific set of lipid parameters, thus limiting its use in membrane protein simulations. In order to overcome this limitation we assessed whether the widely used united-atom lipid parameters described by Berger and co-workers could be used in conjunction with AMBER force fields in simulations of membrane proteins. Thus, free energies of solvation in water and in cyclohexane, and free energies of water to cyclohexane transfer, were computed by thermodynamic integration procedures for neutral amino acid side-chains employing AMBER99, AMBER03, and OPLS-AA amino acid force fields. In addition, MD simulations of three membrane proteins in a POPC lipid bilayer, the β2 adrenergic G protein-coupled receptor, Aquaporin-1, and the outer membrane protein Omp32, were performed with the aim of comparing the AMBER99SB/Berger combination of force fields with the OPLS-AA/Berger combination. We have shown that AMBER99SB and Berger force fields are compatible, they provide reliable free energy estimations relative to experimental values, and their combination properly describes both membrane and protein structural properties. We then suggest that the AMBER99SB/Berger combination is a reliable choice for the simulation of membrane proteins, which links the easiness of ligand parametrization and the ability to reproduce secondary structure of AMBER99SB force field with the largely validated Berger lipid parameters.

Quantitative Structure−Property Relationship (QSPR) Prediction of Solvation Gibbs Energy of Bifunctional Compounds by Recursive Neural Networks

In this paper we apply a recursive neural network (RNN) model to the prediction of the standard Gibbs energy of solvation in water of mono- and polyfunctional organic compounds. The proposed model is able to directly take as input a structured representation of the molecule and to model a direct and adaptive relationship between the molecular structure and the target property. A data set of 339 mono- and polyfunctional acyclic compounds including alkanes, alkenes, alkynes, alcohols, ethers, thiols, thioethers, aldehydes, ketones, carboxylic acids, esters, amines, amides, haloalkanes, nitriles, and nitroalkanes was considered. As a result of the statistical analysis, we obtained for the predictive capability estimated on a test set of molecules a mean absolute residual of about 1 kJ·mol−1 and a standard deviation of 1.8 kJ·mol−1. This results is quite satisfactory by considering the intrinsic difficulty of predicting solvation properties in water of compounds containing more than one functional group.

Charge-charge and cation-π interactions in ligand binding to G protein-coupled receptors

To study the importance of charge–charge and cation-π interactions for the binding of positively charged amine ligands to their receptors, the energies of interaction between [(CH3)4–N]+, [(CH3)3–NH]+, and [(CH3)4–NH3]+ and acetate, as a model of Asp and Glu, and with benzene, as a model of aromatic side chains, were obtained at the MP2/aug-cc-pVDZ level of theory. The free energies of solvation in water were also calculated for the different amines. It was found that, although primary amines form stronger charge–charge interactions with acetate than tertiary or quaternary amines, the difference is not large enough to compensate their higher solvation energy. Quaternary amines show the weakest interaction with acetate. However, their alkyl groups can interact with various aromatic groups, enhancing ligand binding to the receptor. The analysis was completed with MD calculations on amine binding to the G protein-coupled receptors β2AR and CCR5. The calculations on the model systems were found to be in good agreement with the simulations of the ligand-receptor complexes.

Predicting Physical−Chemical Properties of Compounds from Molecular Structures by Recursive Neural Networks

In this paper, we report on the potential of a recently developed neural network for structures applied to the prediction of physical chemical properties of compounds. The proposed recursive neural network (RecNN) model is able to directly take as input a structured representation of the molecule and to model a direct and adaptive relationship between the molecular structure and target property. Therefore, it combines in a learning system the flexibility and general advantages of a neural network model with the representational power of a structured domain. As a result, a completely new approach to quantitative structure-activity relationship/quantitative structure-property relationship (QSPR/QSAR) analysis is obtained. An original representation of the molecular structures has been developed accounting for both the occurrence of specific atoms/groups and the topological relationships among them. Gibbs free energy of solvation in water, Delta(solv)G degrees , has been chosen as a benchmark for the model. The different approaches proposed in the literature for the prediction of this property have been reconsidered from a general perspective. The advantages of RecNN as a suitable tool for the automatization of fundamental parts of the QSPR/QSAR analysis have been highlighted. The RecNN model has been applied to the analysis of the Delta(solv)G degrees in water of 138 monofunctional acyclic organic compounds and tested on an external data set of 33 compounds. As a result of the statistical analysis, we obtained, for the predictive accuracy estimated on the test set, correlation coefficient R = 0.9985, standard deviation S = 0.68 kJ mol(-1), and mean absolute error MAE = 0.46 kJ mol(-1). The inherent ability of RecNN to abstract chemical knowledge through the adaptive learning process has been investigated by principal components analysis of the internal representations computed by the network. It has been found that the model recognizes the chemical compounds on the basis of a nontrivial combination of their chemical structure and target property.

Fluoro-substitution effects in deoxyfluoro- d-glucose derivatives: random conformational search and quantum chemical calculation

The effect of substitution by the fluorine atom at different positions of d-glucose was investigated by quantum chemical calculation of the low-energy conformers. These were obtained through the Random conformational search method. The geometries of conformers were optimized at the RHF/6-31(d) level, then reoptimization and vibrational analysis were performed at the B3LYP/6-31+G(d) level. Single-point energies were calculated at the B3LYP/6-311++G(2d,2p) level. The free energies of solvation in water were calculated utilizing the AM1-SM5.4 solvation model. For all substitution positions, the ring conformation does not change much, and the pyranoid 4 C 1 conformers are dominant, while variations in the substitution site result in different effects in the network of hydrogen bonds, anomeric effect, the solvation free energy, and the ratio of α- and β-anomers.

Surface-Integral QSPR Models: Local Energy Properties

Surface-integral models based on AM1 semiempirical molecular orbital calculations are presented for the free energies of solvation in water, n-octanol, and chloroform and for the enthalpy of solvation in water. A parametrized function of four local properties calculated at the isodensity surface (the molecular electrostatic potential, local ionization energy, electron affinity, and polarizability) is integrated over the triangulated surface area to obtain the target quantity. The resulting models give results only slightly less accurate than those reported for parametrized generalized Born/polar surface area models despite relying only on gas-phase calculations. The water and octanol free-energy models were validated by calculating the water-octanol partition coefficient for a test set of organic compounds with moderate success. The models lead to a local solvation energy, which can be projected onto the molecular isodensity surface and provides insight into "hot" areas for solvation in water or the other solvents.

Group contributions to the solvation free energy from MST continuum calculations

Group contributions to the free energy of solvation in water and octanol as well as to the octanol/water partition coefficient have been determined from Miertus-Scrocco-Tomasi continuum calculations. Particular attention is paid to the influence exerted by the procedure used to carry out the charge normalization in the MST model, as well as to the formalism of the partitioning scheme. A good agreement is found between the group contributions calculated by using different charge normalization and partitioning schemes in a series of structurally related drug-like molecule. Finally, the transferability of the group contributions determined for common chemical fragments along the series of molecules is discussed.

A Computer Simulation of Functional Group Contributions to Free Energy in Water and a DPPC Lipid Bilayer

A series of all-atom molecular dynamics simulations has been performed to evaluate the contributions of various functional groups to the free energy of solvation in water and a dipalmitoylphospatidylcholine lipid bilayer membrane and to the free energies of solute transfer (Δ(Δ G°) X) from water into the ordered-chain interior of the bilayer. Free energies for mutations of the α-H atom in p-toluic acid to six different substituents ( CH 3, Cl, OCH 3, CN, OH, COOH) were calculated by a combined thermodynamic integration and perturbation method and compared to literature results from vapor pressure measurements, partition coefficients, and membrane transport experiments. Convergence of the calculated free energies was indicated by substantial declines in standard deviations for the calculated free energies with increased simulation length, by the independence of the ensemble-averaged Boltzmann factors to simulation length, and the weak dependence of hysteresis effects on simulation length over two different simulation lengths and starting from different initial configurations. Calculated values of Δ(Δ G°) X correlate linearly with corresponding values obtained from lipid bilayer transport experiments with a slope of 1.1 and from measurements of partition coefficients between water and hexadecane or decadiene, with slopes of 1.1 and 0.9, respectively. Van der Waals interactions between the functional group of interest and the acyl chains in the ordered chain region account for more than 95% of the overall potential energy of interaction. These results support the view that the ordered chain region within the bilayer interior is the barrier domain for transport and that solvation interactions within this region resemble those occurring in a nonpolar hydrocarbon.

A widely applicable set of descriptors

Three sets of molecular descriptors computable from connection table information are defined. These descriptors are based on atomic contributions to van der Waals surface area, log P (octanol/water), molar refractivity, and partial charge. The descriptors are applied to the construction of QSAR/QSPR models for boiling point, vapor pressure, free energy of solvation in water, solubility in water, thrombin/trypsin/factor Xa activity, blood-brain barrier permeability, and compound classification. The wide applicability of these descriptors suggests uses in QSAR/QSPR, combinatorial library design, and molecular diversity work.

Investigation of the Anomalous Solvation Free Energies of Amides and Amines: FEP Calculations in Cyclohexane and PS-GVB Calculations on Amide−Water Complexes

Free energy perturbation (FEP) calculations of acetamide, N-methylacetamide, N,N-dimethylacetamide, ammonia, and methylamine in cyclohexane were performed to help rationalize their counterintuitive experimental free energies of solvation in water (i.e., N-methylacetamide is more favorably solvated than acetamide, and methylamine is more favorably solvated than ammonia). Analogously to the aqueous FEP calculations in water carried out previously, the calculations in cyclohexane find an approximately additive methyl substitution effect for both the amides and amines, with, in this case, the most highly methylated molecule most favorably solvated in cyclohexane. PS-GVB calculations at the LMP2/cc-pVDZ level were also performed on the amides and suggest that their anomalous experimental aqueous solvation free energies could be due to differences in their hydrated gas-phase structures.

Free energies of solvation in chloroform and water from a linear response approach

Monte Carlo statistical mechanics simulations were used to compute absolute free energies of solvation in chloroform for 16 organic molecules. The intermolecular interactions were described by classical potential functions consisting of Coulomb and Lennard–Jones interactions. The partial charges for the solutes were derived from fitting to the electrostatic potential surfaces of ab initio 6–31G* wavefunctions. First, free energy perturbation (FEP) calculations yielded relative free energies of solvation. These were converted to absolute quantities through perturbations to the reference molecule, methane, which was annihilated. The average error in the FEP-computed free energies of solvation is 0·8 kcal mol−1. Then, a linear response equation, which contains terms proportional to the Lennard–Jones (van der Waals) and Coulombic components of the solute–solvent energy and to the solvent-accessible surface area of the solute, was optimized and reproduced both the FEP-calculated and experimental free energies of solvation with average errors of ca 0·5 kcal mol−1. In addition, an existing solute dataset for water, which had previously been fitted to the same equation, was expanded from 16 to 35 molecules. The fit of the Monte Carlo results for this set of molecules in TIP4P water to the experimental free energies of hydration yielded an average error of 0·8 kcal mol−1. Combination of the predictions of free energies of solvation in water and chloroform yields partition coefficients, log P, with an average error of 0·3–0·4 log unit. © 1997 John Wiley & Sons, Ltd.

Simulation of the solvation free energies for methane, ethane, and propane and corresponding amino acid dipeptides: a critical test of the bond-PMF correction, a new set of hydrocarbon parameters, and the gas phase-water hydrophobicity scale

We have carried out free energy perturbation calculations to determine the relative free energies of solvation in water for methane, ethane, and propane. Experimentally, the relative solvation free energy of methane and ethane is -0.16±0.01 kcal/mol, and the relative solvation free energy of ethane and propane is 0.17±0.04 kcal/mol