Relative Solvation Free Energies Research Articles

Theoretical in-Solution Conformational/Tautomeric Analyses for Chain Systems with Conjugated Double Bonds Involving Nitrogen(s).

Conformational/tautomeric transformations for X=CH–CH=Y structures (X = CH2, O, NH and Y = NH) have been studied in the gas phase, in dichloromethane and in aqueous solutions. The paper is a continuation of a former study where s-cis/s-trans conformational equilibria were predicted for analogues. The s-trans conformation is preferred for the present molecules in the gas phase on the basis of its lowest internal free energy as calculated at the B97D/aug-cc-pvqz and CCSD(T)CBS (coupled-cluster singles and doubles with non-iterative triples extrapolated to the complete basis set) levels. Transition state barriers are of 29–36 kJ/mol for rotations about the central C–C bonds. In solution, an s-trans form is still favored on the basis of its considerably lower internal free energy compared with the s-cis forms as calculated by IEF-PCM (integral-equation formalism of the polarizable continuum dielectric solvent model) at the theoretical levels indicated. A tetrahydrate model in the supermolecule/continuum approach helped explore the 2solute-solvent hydrogen bond pattern. The calculated transition state barrier for rotation about the C–C bond decreased to 27 kJ/mol for the tetrahydrate. Considering explicit solvent models, relative solvation free energies were calculated by means of the free energy perturbation method through Monte Carlo simulations. These calculated values differ remarkably from those by the PCM approach in aqueous solution, nonetheless the same prevalent conformation was predicted by the two methods. Aqueous solution structure-characteristics were determined by Monte Carlo. Equilibration of conformers/tautomers through water-assisted double proton-relay is discussed. This mechanism is not viable, however, in non-protic solvents where the calculated potential of mean force curve does not predict remarkable solute dimerization and subsequent favorable orientation.

New Insights into Lipid Monolayers from Coarse-Grained Simulation Techniques

New Insights into Lipid Monolayers from Coarse-Grained Simulation Techniques

The CHARMM-TURBOMOLE interface for efficient and accurate QM/MM molecular dynamics, free energies, and excited state properties.

The quantum mechanical (QM)/molecular mechanical (MM) interface between Chemistry at HARvard Molecular Mechanics (CHARMM) and TURBOMOLE is described. CHARMM provides an extensive set of simulation algorithms, like molecular dynamics (MD) and free energy perturbation, and support for mature nonpolarizable and Drude polarizable force fields. TURBOMOLE provides fast QM calculations using density functional theory or wave function methods and excited state properties. CHARMM-TURBOMOLE is well-suited for extended QM/MM MD simulations using first principles methods with large (triple-ζ) basis sets. We demonstrate these capabilities with a QM/MM simulation of Mg(2+) (aq), where the MM outer sphere water molecules are represented using the SWM4-NDP Drude polarizable force field and the ion and inner coordination sphere are represented using QM PBE, PBE0, and MP2 methods. The relative solvation free energies of Mg(2+) and Zn(2+) were calculated using thermodynamic integration. We also demonstrate the features for excited state properties. We calculate the time-averaged solution absorption spectrum of indole, the emission spectrum of the indole 1La excited state, and the electronic circular dichroism spectrum of an oxacepham.

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.

Multiscale Free Energy Simulations: An Efficient Method for Connecting Classical MD Simulations to QM or QM/MM Free Energies Using Non-Boltzmann Bennett Reweighting Schemes.

The reliability of free energy simulations (FES) is limited by two factors: (a) the need for correct sampling and (b) the accuracy of the computational method employed. Classical methods (e.g., force fields) are typically used for FES and present a myriad of challenges, with parametrization being a principle one. On the other hand, parameter-free quantum mechanical (QM) methods tend to be too computationally expensive for adequate sampling. One widely used approach is a combination of methods, where the free energy difference between the two end states is computed by, e.g., molecular mechanics (MM), and the end states are corrected by more accurate methods, such as QM or hybrid QM/MM techniques. Here we report two new approaches that significantly improve the aforementioned scheme; with a focus on how to compute corrections between, e.g., the MM and the more accurate QM calculations. First, a molecular dynamics trajectory that properly samples relevant conformational degrees of freedom is generated. Next, potential energies of each trajectory frame are generated with a QM or QM/MM Hamiltonian. Free energy differences are then calculated based on the QM or QM/MM energies using either a non-Boltzmann Bennett approach (QM-NBB) or non-Boltzmann free energy perturbation (NB-FEP). Both approaches are applied to calculate relative and absolute solvation free energies in explicit and implicit solvent environments. Solvation free energy differences (relative and absolute) between ethane and methanol in explicit solvent are used as the initial test case for QM-NBB. Next, implicit solvent methods are employed in conjunction with both QM-NBB and NB-FEP to compute absolute solvation free energies for 21 compounds. These compounds range from small molecules such as ethane and methanol to fairly large, flexible solutes, such as triacetyl glycerol. Several technical aspects were investigated. Ultimately some best practices are suggested for improving methods that seek to connect MM to QM (or QM/MM) levels of theory in FES.

Theoretical conformational analysis for chain systems with two conjugated double bonds in the gas phase and in solution

Conformational preferences for butadiene-1,3, acrolein, glyoxal, methyl-1-propenyl ketone, acrylic and pyruvic acids with conjugated double-bond substructures have been studied at the IEF-PCM/B97D/aug-cc-pvqz and IEF-PCM/CCSD(T)/CBS theoretical levels in dichloromethane, acetonitrile and water. Overall agreement were achieved by the two quantum mechanical methods with deviations in the relative conformational free energies up to a few tenths of a kcal/mol. Considering explicit-solvent Monte Carlo simulations, the favorable conformations agree with those from IEF-PCM results with an exception for pyruvic acid. Barriers to rotation about the central CC bond were calculated at 1.2–8.5kcal/mol. The conformational equilibria are under thermodynamic control with predominating s-trans form in general.Monte Carlo simulations predict non-negligibly different relative solvation free energies when a reaction field model or the Ewald correction has been applied to account for the long-range electrostatic interactions. Acids favorably adopt the dimeric form with doubly hydrogen-bonded structures in dilute solutions. The calculated degree of association is highly sensitive to the accepted atomic charges, indicating the importance of the polarization of the constituents within the dimer.

Surface Acidity of Water Probed by Free Energy Calculation for Trimethylamine Protonation

Surface acidity/basicity of water has been elusive, due to contradicting observations from various aspects. One effective definition has been proposed by investigating the protonation equilibrium (pKa) of the indicator species at the water surface. We calculated the pKa of trimethylamine at the surface by using quantum mechanics/molecular mechanics (QM/MM) and thermodynamic integration calculations and elucidated the observed pKa shift at the surface. It was revealed that the observed pKa shift reflects specific properties of the indicator species, particularly relative solvation free energy at the surface. The pKa shift appears within ∼5 A thickness. One has to properly take account of the specific indicators toward deriving a general picture of surface acidity/basicity from protonation reactions.

Using binary mixtures of dicationic ionic liquids for determination of activity coefficients at infinite dilution by gas–liquid chromatography

This work is the continuation of our investigation into using dicationic ionic liquids (ILs) as stationary phase in gas chromatography (Tabar Heydar K, Nazifi M, Sharifi A, Mirzaei M, Gharavi H, Ahmadi SH, J. Chromatographia 76 (2013) 165). In this work, the activity coefficients at infinite dilution of 23 various solutes (alkanes, aromatics, alcohols, aldehydes, ketones, amines, chloroalkanes, ethers) have been measured in the two binary mixtures of ILs: 1,12-di(N-methylpyrrolidinium)dodecane–bis(trifluoromethylsulfonyl)imide/1,12-di(3-methylimidazolium)dodecane–bis(trifluoromethylsulfonyl)imide (1:1), [C12(mpy)2]–[(NTf2)2]/[C12(mim)2]–[(NTf2)2] and 1,12-di(N-methylpyrrolidinium)dodecane–bis(trifluoromethylsulfonyl)imide/1,12 di(3-methylimidazolium)dodecane–tetrafluoroborate (1:1), [C12(mpy)2]–[(NTf2)2]/[C12(mim)2]–[(BF4)2], by gas–liquid chromatography (GLC) in the temperature range from 313 to 343K. The same operations were performed on the neat IL: 1, 12-di(N-methylpyrrolidinium)dodecane–bis(trifluoromethylsulfonyl)imide, [C12(mpy)2]–[(NTf2)2] at T=313 and 323K, in order to make a comparison between different ILs.These mixtures of dicationic ILs with different anions and the neat IL have been investigated in this study for the first time. Moreover, the solvation interactions between solvents and solute molecules at 313, 343 and 373K have been determined via Abraham solvation parameter model (linear solvation free energy relationship [LSFER] model). The selectivities for the octane/linear alcohols, octane/polar compounds, cyclohexane/aromatics were obtained from experimental activity coefficient data at 313K, and compared with other ILs from the literature. The result of this comparison confirms that these ILs are potentially excellent solvents for the separation of alkanes/alcohols, alkanes/polar compounds and aliphatic/aromatic mixtures.

Advances in Binding Free Energies Calculations: QM/MM-Based Free Energy Perturbation Method for Drug Design

Multiple approaches have been devised and evaluated to computationally estimate binding free energies. Results using a recently developed Quantum Mechanics (QM)/Molecular Mechanics (MM) based Free Energy Perturbation (FEP) method suggest that this method has the potential to provide the most accurate estimation of binding affinities to date. The method treats ligands/inhibitors using QM while using MM for the rest of the system. The method has been applied and validated for a structurally diverse set of fructose 1,6- bisphosphatase (FBPase) inhibitors suggesting that the approach has the potential to be used as an integral part of drug discovery for both lead identification lead optimization, where there is a structure available. In addition, this QM/MM-based FEP method was shown to accurately replicate the anomalous hydration behavior exhibited by simple amines and amides suggesting that the method may also prove useful in predicting physical properties of molecules. While the method is about 5-fold more computationally demanding than conventional FEP, it has the potential to be less demanding on the end user since it avoids development of MM force field parameters for novel ligands and thereby eliminates this time-consuming step that often contributes significantly to the inaccuracy of binding affinity predictions using conventional FEP methods. The QM/MM-based FEP method has been extensively tested with respect to important considerations such as the length of the simulation required to obtain satisfactory convergence in the calculated relative solvation and binding free energies for both small and large structural changes between ligands. Future automation of the method and parallelization of the code is expected to enhance the speed and increase its use for drug design and lead optimization.

HIV-1 Associated Topoisomerase IIβ Kinase: A Potential Pharmacological Target for Viral Replication

Viruses have been found to exhibit protein kinase activity associated with their purified viral particles. HIV-1 virus particles possess a novel 72 kD protein, Topoisomerase II beta kinase (Topo IIβKHIV) activity. The enzyme, isolated and purified from PEGprecipitated HIV-1 particles, is insensitive against a diverse set of known kinase inhibitors. The pyridine derivatives were found to be active against both Topo IIβKHIV activity and HIV-1 replication. For both kinase antagonism and anti-HIV-1 activity the Comparative Molecular Field Analysis (CoMFA) models were proposed. The CoMFA model was also evaluated independently with a set of test molecules for their anti-viral activity. The kinase inhibition and anti-viral activities for these inhibitors, tested in an in vitro kinase agree with the CoMFA model (cross-validated r2 (q2) value of 0.642 with six principal components), lower acceptable results are obtained with anti- HIV-1 activity (cross-validated r2 (q2) value of 0.358 with four principal components) and also correlate with relative solvation free energy calculations. The predictive power of the models was evaluated with 2 test molecules each and tends to lie within 1 log unit. An in cell validation of the model with a representative inhibitor, 2-methoxypyridine shows its ability to inhibit Topo IIβ phosphorylation during acute HIV-1 infection. Close correlation of molecular fields of inhibitory domains of kinase and HIV-1 inhibitors suggests specificity of action of pyridine derivatives in affecting HIV-1 replication through inhibition of Kinase activity. These investigations suggest that Topo IIβKHIV is a potential target for an effective control of HIV-1 replication that would help in developing new anti-retroviral molecules.

Molecular Dynamics Investigation of Alkali Metal Ions in Liquid and Aqueous Ammonia

A polarizable potential model for M(+)-NH3 interactions (M(+) = Li(+), Na(+), K(+), Rb(+), Cs(+)) is optimized based on the ab initio properties of the ion-ammonia dimers calculated at the MP2 level of theory. The optimized model reproduces the ab initio binding energies of M(+)(NH3)n (n = 2-4) and M(+)(NH3)n(H2O)m (n, m = 1-3 and n + m ≤ 4) clusters and gives relative solvation free energies in liquid ammonia in good agreement with experimental data, without further adjustments. It also reproduces binding cooperativity in ion-ammonia and ion-ammonia-water clusters. The model is used in molecular dynamics simulations of isolated ions in liquid ammonia and in aqueous ammonia solutions with various ammonia molar fractions (0.0 ≤ xNH3 ≤ 1.0). Simulations in liquid ammonia show coordination numbers of 4.0 for Li(+), 5.3 for Na(+), 6.1 for K(+), 6.7 for Rb(+), and 7.7 for Cs(+), in very good agreement with available experimental results. Simulations of ions in aqueous ammonia show preferential solvation by water in their first solvation shells and preferential solvation by ammonia in their second shells. Potentials of mean force are calculated between each ion and NH3 in liquid water, and between each ion and H2O in liquid ammonia. The results suggest that, in liquid water, Li(+) and Na(+) bind NH3 in their second solvation shells only, while Cs(+) binds NH3 in its first solvation shell only (K(+) and Rb(+) ions show only weak affinity for NH3 in water). In liquid ammonia, the ions bind H2O in their first solvation shells with an affinity following the trend Li(+) > Na(+) > K(+) ≈ Rb(+) > Cs(+).

Tuning of the Dienophilic Reactivity of Imidazo[1,2-a]pyridine: A Comparison of DFT and Dispersion-Corrected DFT Calculations

Abstract A comparative study of the DFT calculations with and without dispersion correction for the determination of the relative activation energy barriers and reaction energies of the normal electron demand Diels–Alder (NED DA) reactions of imidazo[1,2-a]pyridine and its derivatives with 1,3-butadiene at the B3LYP/6-31+G** level reveals that on inclusion of the dispersion correction, the relative activation energy barriers are lowered by ca. 10–13 kcal mol−1 whereas relative reaction energies are increased by ca. 9–13 kcal mol−1 as compared to the DFT calculations without dispersion correction. Similar results are obtained for the reverse electron demand (RED) DA reactions of imidazo[1,2-a]pyridine and its derivatives with tetrachloro-o-benzoquinone. The relative free energies of solvation of different species determined from SCRF calculations allow to detect solvent-induced geometry relaxation of the reactant molecules and the transition states which rationalises lowering of the relative activation energies in methylene chloride. The reactions are found to occur without the involvement of the reactants complexes.

Solvent effect on the absorption and fluorescence spectra of 7-acetoxy-6-(2,3-dibromopropyl)-4,8-dimethylcoumarin: Determination of ground and excited state dipole moments

The ground state (μg) and excited state (μe) dipole moments of 7-acetoxy-6-(2,3-dibromopropyl)-4,8-dimethylcoumarin (abbreviated as 7ADDC) are estimated from solvatochromic shifts of absorption and fluorescence spectra as a function of the dielectric constant (ε) and refractive index (n). While the ground state dipole moment is determined by using Bilot–Kawski method, the excited state dipole moment is calculated by using Bilot–Kawski, Lippert–Mataga, Bakhshiev, Kawski–Chamma–Viallet and Reichardt correlation methods. Excited state dipole moment is observed as larger than the ground state dipole moment due to substantial π-electron density redistribution. The ground state and excited state dipole moments are observed as parallel to each other with angle of 0°. Solute–solvent interactions are analyzed by means of linear solvation free energy relationships (LSER) using dielectric constant function (f(ε)), refractive index function (f(n)) and Kamlet–Taft parameters (α and β). Atomic charges, electron densities and molecular orbitals are calculated in vacuum and with solvent effect by using both DFT and TDDFT methods. Solvent accessible surface, molecular electrostatic potential (MEP) and electrostatic potential (ESP) are visualized as a result of DFT calculations.

Theoretical Studies of the Solvent Effect on the Conformation of the HO–C–C–X (X = F, NH2, NO2) Moiety with Competing Intra- and Intermolecular Hydrogen Bonds

Theoretical calculations up to the ab initio IEF-PCM/CCSD(T)/CBS//IEF-PCM/B3LYP/6-311++G** and IEF-PCM/B97D/aug-cc-pvtz levels have been performed for 2X-ethanol and 2X-phenol systems with X = F, NH(2), NO(2) in chloroform and aqueous solution. The calculated relative free energies by means of the IEF-PCM continuum dielectric method do not differ very much at the DFT and ab initio levels. Application of explicit solvent models and the FEP/MC method for determining relative solvation free energies causes, however, large deviations in the predicted equilibrium compositions, although the predominant conformation for the solute is generally in agreement with that from the corresponding IEF-PCM calculations. Existence of an intramolecular hydrogen bond (HB structure) for species with the HO-C-C-X moiety is preferred compared with a conformation when the hydrogen bond is disrupted (NoHB) for the considered F- and NO(2)-substituted molecules both in chloroform and aqueous solution. For 2NH(2)-ethanol, the HB structure is predominant in chloroform, whereas the 93:7 ratio for the OCCN trans/gauche species was obtained in aqueous solution. 2NH(2)-phenol exhibits a subtle equilibrium of the HB and NoHB conformations in both solvents. Potential of mean force calculations predict about a 10% solute association for the trans 2NH(2)-ethanol solute even in the fairly dilute 0.22 molar solution, whereas direct MC simulations do not support the maintenance of a doubly hydrogen-bonded dimer. Aqueous solution characteristics, as coordination numbers and numbers of strongly bound water molecules to the solute at T = 298 K and p = 1 atm, correspond reasonably to the derived molecular structures.

Alchemical Free Energy Differences in Flexible Molecules from Thermodynamic Integration or Free Energy Perturbation Combined with Driven Adiabatic Dynamics.

Alchemical free energy simulations are commonly used to calculate relative binding or solvation free energies in molecular systems. The convergence of alchemical free energy calculations is often hampered by inefficient sampling of the conformational degrees of freedom, which remain trapped in metastable substates. Here, we show that thermodynamic integration (TI) or free energy perturbation (FEP) can be combined with the recent driven adiabatic free energy dynamics (dAFED) method, in order to enhance conformational sampling along a set of chosen collective variables. The resulting TI-dAFED or FEP-dAFED methods are validated on a two-dimensional analytical problem. The ability of these methods to provide accurate free energy differences for realistic molecular systems is demonstrated by calculating the enantiomerization free energy of the alanine dipeptide in explicit solvent.

On the Interaction of Aliphatic Amines and Ammonium Ions with Carboxylic Acids in Solution and in Receptor Pockets

Association energies of the acetate ion with cationic amines bearing one to three methyl groups were calculated in the range of -14 to -17 kcal/mol in aqueous solution by means of the IEF-PCM method at the CCSD(T)/CBS//MP2/aug-cc-pvdz and DFT/B97D/CBS//B97D/aug-cc-pvtz levels. The main stabilization factor for the association is the possibility for the formation of an ionic intermolecular hydrogen bond between the elements of the complex. For a quaternary ammonium ion, the favorable electrostatic interaction energy is the only driving force, and the stabilization energy for the complex is reduced to -4 kcal/mol. The internal free energies of the ion-pair tautomers of the studied species are higher by 10-15 kcal/mol in water than those for the neutral, hydrogen-bonded forms. Monte Carlo free energy perturbation calculations at T = 298 K and p = 1 atm predict -11 to -16 kcal/mol relative solvation free energy in favor of the corresponding ionic form. As a result, the ion-pair tautomer is the prevailing form in aqueous solution and on the extracellular surface of a receptor. Modeling the complex of a protonated ligand interacting with an Asp/Glu carboxylate side-chain in the binding cavity of a receptor, two strongly bound water molecules were considered so as to form hydrogen-bonded water bridges between the elements of the ion-pair. Nonetheless, the low polarity environment mimicked by a chloroform solvent cannot stabilize the ionic tautomer. A proton jump was predicted, which suggests that acetylcholine, an inherent cation by structure, might have evolved as the natural agonist for muscarinic receptors because a quaternary ammonium system assures the maintenance of the ion-pair form with a carboxylate side-chain in a protein cavity, the latter perhaps then being needed for receptor activation.

Structural and spectroscopic study of Al(III)–3-hydroxyflavone complex: Determination of the stability constants in water–methanol mixtures

Stoichiometry and apparent stability constant (KC) of the complex formed between Al(III) and 3-hydroxyflavone were determined in methanol and water–methanol mixtures (% water w/w: 3.11; 6.15; 10.4; 15.2; 19.9 and 25.3) by UV–vis spectroscopy at 25.0°C and constant ionic strength (0.05M, sodium chloride). Stoichiometry of the complex (1:2, metal:ligand) is not modified with an increase in water percentage in the analyzed interval. The value of KC in methanol is greater than in the binary solutions. The effects of changing solvent composition on KC data were explained by linear solvation free energy relationships using the solvatochromic parameter of Kamlet and Taft (α, β and π*). Multiple linear regression analysis indicates that the hydrogen bond donating ability (α) of the solvent and non-specific interactions (π*) play an important role in the degree of occurrence of the reaction. The effect of temperature on KC was also analyzed by assessing standard entropy and enthalpy variations of the reaction in methanol. Finally, the structure of the complex was investigated using FTIR spectroscopy and DFT calculations. The ligand exhibits small structural changes upon complexation, localized on the chelating site. The calculated vibrational frequencies of the complex were successfully compared against the experimental values.

Effects of intramolecular hydrogen bonding and solvent composition on acidity of some dihydroxy-thioxanthone derivatives in methanol–water binary solvents

► The acidity constant of some new dihydroxy thioxanthone derivatives was determined. ► The effect of inter and intra hydrogen bonding on acidity constants were explained. ► The effect of solvent composition (methanol–water) was also investigated. ► 1,3-Dihydroxy derivative unexpectably showed one ionization step. ► The findings of this article are of especial importance for analytical applications. The acidity constant of four recently synthesized dihydroxy-thioxanthone derivatives (i.e., 1,4-dihydroxy; A1, 3-methyl-1,4-dihydroxy; A2, 2,3-dihydroxy; A3 and 1,3-dihydroxy; A4) in methanol–water binary mixed solvents were determined by multivariate analysis of spectrophotometric-pH-metric data. The solutes A1, A2 and A3 exhibited two ionization steps whereas one ionization step was observed for A4, attributed to the strong intramolecular hydrogen-bonding formed between the hydrogen of 1-hydroxy and its neighbor carbonyl group. The effects of molecular structure on the acid–base behavior of solutes were discussed mainly based on intra and intermolecular hydrogen bonding. The effects of solvent composition on the acidity constant were explained through linear solvation free energy relationship (LSFER) study. It was found that each ionization step of each solute can be modeled by different reduced models of Kamlet–Taft, proposing that they behave differently. Finally, the effect of solvent composition on the calculated pure absorption spectra of the different acid–base species was investigated.

Use of a QM/MM-Based FEP Method to Evaluate the Anomalous Hydration Behavior of Simple Alkyl Amines and Amides: Application to the Design of FBPase Inhibitors for the Treatment of Type-2 Diabetes

Standard molecular mechanics (MM) force fields predict a nearly linear decrease in hydration free energy with each successive addition of a methyl group to ammonia or acetamide, whereas a nonadditive relationship is observed experimentally. In contrast, the non-additive hydration behavior is reproduced directly using a quantum mechanics (QM)/MM-based free-energy perturbation (FEP) method wherein the solute partial atomic charges are updated at every window. Decomposing the free energies into electrostatic and van der Waals contributions and comparing the results with the corresponding free energies obtained using a conventional FEP method and a QM/MM method wherein the charges are not updated suggests that inaccuracies in the electrostatic free energies are the primary reason for the inability of the conventional FEP method to predict the experimental findings. The QM/MM-based FEP method was subsequently used to evaluate inhibitors of the diabetes drug target fructose-1,6-bisphosphatase adenosine 5'-monophosphate and 6-methylamino purine riboside 5'-monophosphate. The predicted relative binding free energy was consistent with the experimental findings, whereas the relative binding free energy predicted using the conventional FEP method differed from the experimental finding by an amount consistent with the overestimated relative solvation free energies calculated for alkylamines. Accordingly, the QM/MM-based FEP method offers potential advantages over conventional FEP methods, including greater accuracy and reduced user input. Moreover, since drug candidates often contain either functionality that is inadequately treated by MM (e.g., simple alkylamines and alkylamides) or new molecular scaffolds that require time-consuming development of MM parameters, these advantages could enable future automation of FEP calculations as well as greatly increase the use and impact of FEP calculations in drug discovery.

Aggregation of imidazolium based ionic liquids in binary methanol–water solvents: A linear solvation free energy relationship study

Aggregation behavior of an imidazolium based ionic liquid (IL), namely 1-dodecyl-3-methylimidazolium chloride [C 12mim][Cl] and a surfactant with the same aliphatic chain, dodecyl trimethylammonium chloride (DTAC), are studied and compared in different mole fractions of methanol–water binary solvents using conductometry. From the conductivity data, micellar parameters including critical micelle concentration (CMC), degree of counter ion dissociation (α) and Gibbs free energy of micellization (ΔG°mic) for both species were calculated as a function of methanol mole fraction. It was found that similar to the surfactant DTAC, the ionic liquid [C 12mim][Cl] forms micellar aggregation in pure water and methanol as well as in their binary mixtures. The CMC values for both compounds were increased up to a methanol mole fraction of 0.5 and then decreased at higher mole fractions. This was attributed to the preferential solvation and formation of methanol–water cluster in binary mixed solvents. The changes in CMC of [C 12mim][Cl] and DTAC as a function of methanol mole fraction were also described by changing in solvatochromic properties of solvents through linear solvation free energy relationship (LSFER) study. A linear relationship between log (CMC) and two solvatochromic Kamlet-Taff parameters including polarity/polarizability (π*) and hydrogen-bond basicity (β) was observed.