The SAMPL6 challenge on predicting aqueous p<Emphasis Type="Italic">K</Emphasis><Subscript>a</Subscript> values from EC-RISM theory

The “embedded cluster reference interaction site model” (EC-RISM) integral equation theory is applied to the problem of predicting aqueous pK_a values for drug-like molecules based on an ensemble of tautomers. EC-RISM is based on self-consistent calculations of a solute’s electronic structure and the distribution function of surrounding water. Following-up on the workflow developed after the SAMPL5 challenge on cyclohexane-water distribution coefficients we extended and improved the methodology by taking into account exact electrostatic solute–solvent interactions taken from the wave function in solution. As before, the model is calibrated against Gibbs energies of hydration from the “Minnesota Solvation Database” and a public dataset of acidity constants of organic acids and bases by adjusting in total 4 parameters, among which only 3 are relevant for predicting pK_a values. While the best-performing training model yields a root-mean-square error (RMSE) of 1 pK unit, the corresponding test set prediction on the full SAMPL6 dataset of macroscopic pK_a values using the same level of theory exhibits slightly larger error (1.7 pK units) than the best test set model submitted (1.7 pK units for corresponding training set vs. test set performance of 1.6). Post-submission analysis revealed a number of physical optimization options regarding the numerical treatment of electrostatic interactions and conformational sampling. While the experimental test set data revealed after submission was not used for reparametrizing the methodology, the best physically optimized models consequentially result in RMSEs of 1.5 if only improved electrostatic interactions are considered and of 1.1 if, in addition, conformational sampling accounts for quantum-chemically derived rankings. We conclude that these numbers are probably near the ultimate accuracy achievable with the simple 3-parameter model using a single or the two best-ranking conformations per tautomer or microstate. Finally, relations of the present macrostate approach to microstate pK_a results are discussed and some illustrative results for microstate populations are presented.     

Absolute and relative p<Emphasis Type="Italic">K</Emphasis><Subscript>a</Subscript> predictions via a DFT approach applied to the SAMPL6 blind challenge

In this work, quantum mechanical methods were used to predict the microscopic and macroscopic pK_a values for a set of 24 molecules as a part of the SAMPL6 blind challenge. The SMD solvation model was employed with M06-2X and different basis sets to evaluate three pK_a calculation schemes (direct, vertical, and adiabatic). The adiabatic scheme is the most accurate approach (RMSE?=?1.40 pK_a units) and has high correlation (R²?=?0.93), with respect to experiment. This approach can be improved by applying a linear correction to yield an RMSE of 0.73 pK_a units. Additionally, we consider including explicit solvent representation and multiple lower-energy conformations to improve the predictions for outliers. Adding three water molecules explicitly can reduce the error by 2–4 pK_a units, with respect to experiment, whereas including multiple local minima conformations does not necessarily improve the pK_a prediction.     

The SAMPL5 challenge for embedded-cluster integral equation theory: solvation free energies,aqueous p<Emphasis Type="Italic">K</Emphasis><Subscript>a</Subscript>, and cyclohexane–water log <Emphasis Type="Italic">D</Emphasis>

We predict cyclohexane–water distribution coefficients (log D _7.4) for drug-like molecules taken from the SAMPL5 blind prediction challenge by the “embedded cluster reference interaction site model” (EC-RISM) integral equation theory. This task involves the coupled problem of predicting both partition coefficients (log P) of neutral species between the solvents and aqueous acidity constants (pK _a) in order to account for a change of protonation states. The first issue is addressed by calibrating an EC-RISM-based model for solvation free energies derived from the “Minnesota Solvation Database” (MNSOL) for both water and cyclohexane utilizing a correction based on the partial molar volume, yielding a root mean square error (RMSE) of 2.4 kcal mol^?1 for water and 0.8–0.9 kcal mol^?1 for cyclohexane depending on the parametrization. The second one is treated by employing on one hand an empirical pK _a model (MoKa) and, on the other hand, an EC-RISM-derived regression of published acidity constants (RMSE of 1.5 for a single model covering acids and bases). In total, at most 8 adjustable parameters are necessary (2–3 for each solvent and two for the pK _a) for training solvation and acidity models. Applying the final models to the log D _7.4 dataset corresponds to evaluating an independent test set comprising other, composite observables, yielding, for different cyclohexane parametrizations, 2.0–2.1 for the RMSE with the first and 2.2–2.8 with the combined first and second SAMPL5 data set batches. Notably, a pure log P model (assuming neutral species only) performs statistically similarly for these particular compounds. The nature of the approximations and possible perspectives for future developments are discussed.     

Extended solvent-contact model approach to blind SAMPL5 prediction challenge for the distribution coefficients of drug-like molecules

The performance of the extended solvent-contact model has been addressed in the SAMPL5 blind prediction challenge for distribution coefficient (LogD) of drug-like molecules with respect to the cyclohexane/water partitioning system. All the atomic parameters defined for 41 atom types in the solvation free energy function were optimized by operating a standard genetic algorithm with respect to water and cyclohexane solvents. In the parameterizations for cyclohexane, the experimental solvation free energy (ΔG _sol ) data of 15 molecules for 1-octanol were combined with those of 77 molecules for cyclohexane to construct a training set because ΔG _sol values of the former were unavailable for cyclohexane in publicly accessible databases. Using this hybrid training set, we established the LogD prediction model with the correlation coefficient (R), average error (AE), and root mean square error (RMSE) of 0.55, 1.53, and 3.03, respectively, for the comparison of experimental and computational results for 53 SAMPL5 molecules. The modest accuracy in LogD prediction could be attributed to the incomplete optimization of atomic solvation parameters for cyclohexane. With respect to 31 SAMPL5 molecules containing the atom types for which experimental reference data for ΔG _sol were available for both water and cyclohexane, the accuracy in LogD prediction increased remarkably with the R, AE, and RMSE values of 0.82, 0.89, and 1.60, respectively. This significant enhancement in performance stemmed from the better optimization of atomic solvation parameters by limiting the element of training set to the molecules with experimental ΔG _sol data for cyclohexane. Due to the simplicity in model building and to low computational cost for parameterizations, the extended solvent-contact model is anticipated to serve as a valuable computational tool for LogD prediction upon the enrichment of experimental ΔG _sol data for organic solvents.     

p<Emphasis Type="Italic">K</Emphasis><Subscript>a</Subscript> measurements for the SAMPL6 prediction challenge for a set of kinase inhibitor-like fragments

Determining the net charge and protonation states populated by a small molecule in an environment of interest or the cost of altering those protonation states upon transfer to another environment is a prerequisite for predicting its physicochemical and pharmaceutical properties. The environment of interest can be aqueous, an organic solvent, a protein binding site, or a lipid bilayer. Predicting the protonation state of a small molecule is essential to predicting its interactions with biological macromolecules using computational models. Incorrectly modeling the dominant protonation state, shifts in dominant protonation state, or the population of significant mixtures of protonation states can lead to large modeling errors that degrade the accuracy of physical modeling. Low accuracy hinders the use of physical modeling approaches for molecular design. For small molecules, the acid dissociation constant (pK_a) is the primary quantity needed to determine the ionic states populated by a molecule in an aqueous solution at a given pH. As a part of SAMPL6 community challenge, we organized a blind pK_a prediction component to assess the accuracy with which contemporary pK_a prediction methods can predict this quantity, with the ultimate aim of assessing the expected impact on modeling errors this would induce. While a multitude of approaches for predicting pK_a values currently exist, predicting the pK_as of drug-like molecules can be difficult due to challenging properties such as multiple titratable sites, heterocycles, and tautomerization. For this challenge, we focused on set of 24 small molecules selected to resemble selective kinase inhibitors—an important class of therapeutics replete with titratable moieties. Using a Sirius T3 instrument that performs automated acid–base titrations, we used UV absorbance-based pK_a measurements to construct a high-quality experimental reference dataset of macroscopic pK_as for the evaluation of computational pK_a prediction methodologies that was utilized in the SAMPL6 pK_a challenge. For several compounds in which the microscopic protonation states associated with macroscopic pK_as were ambiguous, we performed follow-up NMR experiments to disambiguate the microstates involved in the transition. This dataset provides a useful standard benchmark dataset for the evaluation of pK_a prediction methodologies on kinase inhibitor-like compounds.     

Investigation of Solution p<Emphasis Type="Italic">K</Emphasis><Subscript>a</Subscript> and Thermodynamic Values of Lamivudine and Pefloxacin Drugs by Ab initio and DFT Methods

In this work we investigate the thermodynamic properties and pK_a value of lamivudine and pefloxacin drugs, in aqueous solutions, by ab initio and density functional theory (DFT) methods at different temperatures. Molecular structures and solute–solvent effects of the anions, cations, and neutral molecules of lamivudine and pefloxacin were studied by the polarizable continuum model (PCM). The calculation was done at the DFT-B3LYP/6-31+G(d) level of theory using Tomasi’s method to analyze the formation of intermolecular hydrogen bonds (IHB) in aqueous solution. The pK_a1 values of lamivudine and pK_a2 values of pefloxacin increase with temperature increase. In contrast, the pK_a1 values of pefloxacin decrease when the temperature increases. Further, the thermodynamic properties of the ionization processes (?H, ?S and ?G) of the drugs in aqueous solution were determined and discussed. The results of this work are in good agreement with the literature data at 298.15 K.     

Crystal structure of KPb<Subscript>2</Subscript>Cl<Subscript>5</Subscript> and KPb<Subscript>2</Subscript>Br<Subscript>5</Subscript>

The KPb₂Cl₅ and KPb₂Br₅ crystals are monoclinic (P2₁/c) with a microtwinned structure. X-ray analysis of chloride resulted in the parameters a = 8.854(2) Å, b = 7.927(2) Å, c = 12.485(3) Å; β = 90.05(3)°, d_calc = 4.78(1) g/cm³ (STOE STADI4, MoK_α, 2θ_max = 80°), R₁ = 0.0702 for 4094 F ≥ 4 σ(F) reflections. For bromide, a = 9.256(2) Å, b = 8.365(2) Å, c = 13.025(3) Å; β = 90.00(3)°, d_calc = 5.62(1) g/cm³ (Bruker P4, MoK_α, 2θ_max = 70°), R₁ = 0.0692 for 3076 F ≥ 4 (F) reflections.     

High-pressure defect phase La<Subscript>x</Subscript>Cu<Subscript>3</Subscript>V<Subscript>4</Subscript>O<Subscript>12</Subscript>

Perovskite-like nonstoichiometric oxide La _x Cu₃V₄O₁₂ (space group Im \(\bar 3\), Z = 2, a = 7.313–7.354 Å) with cation-site vacancies has been prepared for the first time at high pressures (p = 6.0–8.0 GPa) and high temperatures (T = 700–1100°C). The compound has metal-type conductivity and paramagnetic properties, and undergoes a phase transition.     

X-ray diffraction study of CsZn<Subscript>2</Subscript>Br<Subscript>5</Subscript>

CsZn₂Br₅ crystals are studied by X-ray diffraction. The compound crystallizes in the monoclinic system with the unit cell parameters a = 6.8880(12) Å, b = 10.4703(19) Å, c = 6.5197(9) Å, β = 108.25°, V = 446.55 ų, ρ_calcd = 4.960 g/cm³. Refractive indices are n _p = 1.640 and n _p = 1.754.     

Synthesis and crystal structure of ternary molybdate compound K<Subscript>5</Subscript>Pb<Subscript>0.5</Subscript>Hf<Subscript>1.5</Subscript>(MoO<Subscript>4</Subscript>)<Subscript>6</Subscript>

Single crystals of triple molybdate of composition 5:1:3 K₅Pb_0.5Hf_1.5(MoO₄)₆ have been grown and their crystal structure has been solved from X-ray diffraction data (an automated diffractometer X8 APEX, MoK _α -radiation, 2173 F(hkl), R = 0.0321). Trigonal unit cell parameters are: a = b = 10.739(2) Å, c = 37.933(9) Å; V = 3789(1) ų, Z = 6, ρ_calc = 4.014 g/cm³, space group \(R\bar 3\). Three-dimensional mixed framework of the structure is formed by two types of MoO₄ tetrahedra and Pb and Hf octahedra linking via common O-vertices. Potassium atoms of three types occupy large vacancies in the framework.     

High-pressure defect phase Nd<Subscript><Emphasis Type="Italic">x</Emphasis></Subscript>Cu<Subscript>3</Subscript>V<Subscript>4</Subscript>O<Subscript>12</Subscript>

A perovskite-like oxide Nd _x Cu₃V₄O₁₂ (space group Im \(\bar 3\) Z = 2, a = 7.278–7.322 Å) with cationic vacancies was prepared for the first time under triaxial compression of p = 6.0–9.0 GPa at 700–1300°C. The compound has a metal-type conductivity, paramagnetic properties, and a phase transition.     

Structure and properties of Ce<Subscript>3</Subscript>Pd<Subscript>3</Subscript>Bi<Subscript>4</Subscript>, CePdBi,and CePd<Subscript>2</Subscript>Zn<Subscript>3</Subscript>

The intermetallic cerium compounds Ce₃-Pd₃Bi₄, CePdBi, and CePd₂Zn₃ were synthesized from the elements in sealed tantalum ampoules in an induction furnace. The compounds were characterized by X-ray powder and single crystal diffraction: CeCo₃B₂ type (ordered version of CaCu₅), P6/mmm, a = 538.4(4), c = 427.7(4) pm, wR2 = 0.0540, 115 F ² values, 9 variables for CePd₂Zn₃ and Y₃Au₃Sb₄ type, I \({\bar 4}\)3d, a = 1005.2(2) pm, w R2 = 0.0402, 264 F ² values, 9 variables for Ce₃Pd₃Bi₄, and MgAgAs type, a = 681.8(1) pm for CePdBi. The bismuthide structures are build up from three-dimensional networks of corner-sharing PdBi₄ tetrahedra with Pd–Bi distances of 281 (Ce₃Pd₃Bi₄) and 296?pm (CePdBi), respectively. The cerium atoms are located in larger voids of coordination number 12 (Ce₃Pd₃Bi₄) and 10 (CePdBi). In CePd₂Zn₃ the cerium atoms fill larger channels within the three-dimensional [Pd₂Zn₃] network with 18 (6 Pd + 12 Zn) nearest neighbors. The three compounds contain stable trivalent cerium with experimental magnetic moments of μ_eff = 2.70(2), 2.48(1), and 2.49(1) μ_B/Ce atom for CePd₂Zn₃, Ce₃Pd₃Bi₄, and CePdBi, respectively. Susceptibility and specific heat data gave no hint for magnetic ordering down to 2.1?K.     

High-pressure nonstoichiometric phase Sm<Subscript><Emphasis Type="Italic">x</Emphasis></Subscript>Cu<Subscript>3</Subscript>V<Subscript>4</Subscript>O<Subscript>12</Subscript>

Perovskite-like nonstoichiometric oxide Sm _x Cu₃V₄O₁₂ (space group Im \(\bar 3\), Z = 2, a = 7.276?7.314 Å) with cationic vacancies and a homogeneity region was prepared barothermally (p = 6.0?9.0 GPa, T = 700?1100°C) for the first time. Structural and isotropic thermal parameters, as well as bond lengths and bond angles, were determined. The compound has metal-type conductivity and paramagnetic properties.     

Crystal structures of Ti(NH<Subscript>4</Subscript>)<Subscript>2</Subscript>P<Subscript>4</Subscript>O<Subscript>13</Subscript> and Sn(NH<Subscript>4</Subscript>)<Subscript>2</Subscript>P<Subscript>4</Subscript>O<Subscript>13</Subscript>

The characteristics of crystal structures of the titanium(IV) diammonium (Ti(NH₄)₂P₄O₁₃) and tin(IV) diammonium (Sn(NH₄)₂P₄O₁₃) tetraphosphates, which are isostructural with similar silicon(IV) and germanium(IV) salts, have been obtained by the Rietveld method using X-ray powder diffraction data. The compounds crystallize in the triclinic system, space group P \(\overline 1 \), Z = 2, a = 15.0291(7) Å, b = 7.9236(4) Å, c = 5.0754(3) Å, α = 99.168(3)°, β = 97.059(3)°, γ = 83.459(3)° for Ti(NH₄)₂P₄O₁₃ and a = 15.1454(7) Å, b = 8.0103(5) Å, c = 5.1053(3) Å, α = 99.898(6)°, β = 96.806(3)°, γ = 83.881(4)° for Sn(NH₄)₂P₄O₁₃. The structure is refined in the isotropic approximation using the pseudo-Voigt function: R _p = 0.077, R _Bragg = 0.045, R _F = 0.057 for Ti(NH₄)₂P₄O₁₃; R _p = 0.082, R _Bragg = 0.044, R _F = 0.046 for Sn(NH₄)₂P₄O₁₃. The hydrogen atoms of the ammonium cations are placed in the calculated positions. A comparative analysis of the structures of the compounds of the M^IV(NH₄)₂P₄O₁₃ (M^IV = Si, Ge, Ti, Sn) series has been carried out.     

Electronic energy structure of As<Subscript>2</Subscript>S<Subscript>3</Subscript>, AsSI,AgAsS<Subscript>2</Subscript>, and TiS<Subscript>2</Subscript> semiconductors

Quantum-mechanical calculations with the FEFF8 code were used to study the electronic energy structure of 200-atomic clusters of As₂S₃, AsSI, AgAsS₂, and TiS₂ semiconductor compounds. The calculated local partial densities of electronic states are compared with the sulfur K and L X-ray emission spectra and sulfur K absorption spectra for fine powders of these compounds. Good agreement between theory and experiment has been obtained.     

Crystal structure of Iron(III) hydrogen diphosphate FeHP<Subscript>2</Subscript>O<Subscript>7</Subscript>

The crystal structure of the β modification of iron(III) hydrogen diphosphate FeHP₂O₇ has been refined by the Rietveld method using powder X-ray diffraction data. The compound crystallizes in the monoclinic system, space group P2₁/n, Z = 4, a = 7.9756(1) Å, b = 12.8260(2) Å, c = 4.8664(6) Å, β = 98.6404(8)°, V = 492.16(1) ų. The structure was refined in the isotropic approximation (pseudo-Voigt function), R _p = 0.024, R _wp = 0.033, R _Bragg = 0.091, R _F = 0.067, and compared with the structures of other compounds M^IIIHP₂O₇ (M^III is a trivalent metal).     

High-pressure defect phase Tm<Subscript><Emphasis Type="Italic">x</Emphasis></Subscript>Cu<Subscript>3</Subscript>V<Subscript>4</Subscript>O<Subscript>12</Subscript>

Perovskite-related oxide Tm _x Cu₃V₄O₁₂ (space group Im \(\bar 3\), Z = 2, a = 7.262?7.273 Å) with vacancies in the cationic sublattice has been prepared for the first time under barothermal conditions (p = 7.0?9.0 GPa, T = 900?1100°C). Electric resistivity (10–300 K) and magnetic susceptibility (0–300 K) were studied as a function of temperature. Tm _x Cu₃V₄O₁₂ is shown to have a metallic conductivity and paramagnetism.     

Ab Initio Theoretical Studies on the Kinetics of Hydrogen Abstraction Type Reactions of Hydroxyl Radicals with CH<Subscript>3</Subscript>CCl<Subscript>2</Subscript>F and CH<Subscript>3</Subscript>CClF<Subscript>2</Subscript>

The hydrogen abstraction reactions from CH₃Cl₂F (R-141b) and CH₃CClF₂ (R-142b) by OH radicals are studied theoretically by semi-classical transition state theory. The stationary points for the reactions are located by using KMLYP density functional method along with 6-311++G(2d,2p) basis set and MP2 method along with 6-311+G(d,p) basis set. Single-point energy calculations are performed by the CBS-Q and G4 combination methods on the geometries optimized at the KMLYP/6-311++G(2d,2p) level of theory. Vibrational anharmonicity coefficients, x _ij , which are needed for semi-classical transition state theory calculations, are computed at the KMLYP/6-311++G(2d,2p) and MP2/6-311+G(d,p) levels of theory. The computed barrier heights are slightly sensitive to the quantum-chemical method. Thermal rate coefficients are computed over the temperature range from 200 to 2000 K and they are shown to be in accordance with available experimental data. On the basis of the computed rate coefficients, the tropospheric lifetime of the CH₃CCl₂F and CH₃CClF₂ are estimated to be about 6.5 and 12.0 years, respectively.     

Resonant photoemission and absorption spectroscopy study of the Cu<Subscript><Emphasis Type="Italic">x</Emphasis></Subscript>TiSe<Subscript>2</Subscript> electronic structure

The Cu3p and Cu2p resonance photoelectron spectra of the valence bands and core levels as well as Ti and CuL _2,3 absorption spectra for monocrystals 1T-Cu _x TiSe₂ were studied. The valence spectra obtained at Cu3p and Cu2p resonance drastically differ from each other. For Cu 3p-3d resonance, there are several bands corresponding to different channels of excited state decay. Spectra of the valence bands at Cu 2p-3d resonance are virtually identical to the spectra of pure TiSe₂. As follows from the absorption spectra, titanium atoms have the oxidation state 4+, whereas copper atoms are close to the free ion state.     

A novel metal chalcogenide: HgCd<Subscript>4</Subscript>S<Subscript>5</Subscript>

A novel metal chalcogenide HgCd₄S₅ (1) was synthesized from solid-state reactions and structurally characterized. Compound 1 crystallizes in the space group C222₁ of the orthorhombic system with four formula units in a cell: a = 12.5661(5) Å, b = 7.2551(5) Å, c = 10.7520(7) Å, V = 980.2(1) ų, Cd₄HgS₅, M _r = 810.49, D _c = 5.492 g/cm³, S = 1.010, μ(MoK _α) = 25.128 mm^?1, F(000) = 1408, R = 0.0611 and wR = 0.1495. Compound 1 is characterized by a 3-D cadmium sulfide framework structure with the infinite mercury sulfide chains located in the cavities.