Polarizable Continuum Solvation Model Research Articles

Phosphonate Chelators for Medicinal Metal Ions.

A family of phosphonate-bearing chelators was synthesized to study their potential in metal-based (radio)pharmaceuticals. Three ligands (H6phospa, H6dipedpa, H6eppy; structures illustrated in manuscript) were fully characterized, including X-ray crystallographic structures of H6phospa and H6dipedpa. NMR spectroscopy techniques were used to confirm the complexation of each ligand with selected trivalent metal ions. These methods were particularly useful in discerning structural information for Sc3+ and La3+ complexes. Solution studies were conducted to evaluate the complex stability of 15 metal complexes. As a general trend, H6phospa was noted to form the most stable complexes, and H6eppy associated with the least stable complexes. Moreover, In3+ complexes were determined to be the most stable, and complexes with La3+ were the least stable, across all metals. Density functional theory (DFT) was employed to calculate structures of H6phospa and H6dipedpa complexes with La3+ and Sc3+. A comparison of experimental 1H NMR spectra with calculated 1H NMR spectra using DFT-optimized structures was used as a method of structure validation. It was noted that theoretical NMR spectra were very sensitive to a number of variables, such as ligand configuration, protonation state, and the number/orientation of explicit water molecules. In general, the inclusion of an explicit second shell of water molecules qualitatively improved the agreement between theoretical and experimental NMR spectra versus a polarizable continuum solvent model alone. Formation constants were also calculated from DFT results using potential-energy optimized structures. Strong dependence of molecular free energies on explicit water molecule number, water molecule configuration, and protonation state was observed, highlighting the need for dynamic data in accurate first-principles calculations of metal-ligand stability constants.

Lipophilic ion aromaticity is not important for permeability across lipid membranes

To clarify the contribution of charge delocalization in a lipophilic ion to the efficacy of its permeation through a lipid membrane, we compared the behavior of alkyl derivatives of triphenylphosphonium, tricyclohexylphosphonium and trihexylphosphonium both in natural and artificial membranes. Exploring accumulation of the lipophilic cations in response to inside-negative membrane potential generation in mitochondria by using an ion-selective electrode revealed similar mitochondrial uptake of butyltricyclohexylphosphonium (C4TCHP) and butyltriphenylphosphonium (C4TPP). Fluorescence correlation spectroscopy also demonstrated similar membrane potential-dependent accumulation of fluorescein derivatives of tricyclohexyldecylphosphonium and decyltriphenylphosphonium in mitochondria. The rate constant of lipophilic cation translocation across the bilayer lipid membrane (BLM), measured by the current relaxation method, moderately increased in the following sequence: trihexyltetradecylphosphonium ([P6,6,6,14]) < triphenyltetradecylphosphonium (C14TPP) < tricyclohexyldodecylphosphonium (C12TCHP). In line with these results, measurements of the BLM stationary conductance indicated that membrane permeability for C4TCHP is 2.5 times higher than that for C4TPP. Values of the difference in the free energy of ion solvation in water and octane calculated using the density functional theory and the polarizable continuum solvent model were similar for methyltriphenylphosphonium, tricyclohexylmethylphosphonium and trihexylmethylphosphonium. Our results prove that both cyclic and aromatic moieties are not necessary for lipophilic ions to effectively permeate through lipid membranes.

Antioxidative Action of Ellagic Acid-A Kinetic DFT Study.

Although one can find numerous studies devoted to the investigation of antioxidative activity of ellagic acid (EA) in the scientific literature, the mechanisms of its action have not yet been fully clarified. Therefore, further kinetic studies are needed to understand its antioxidative capacity completely. This work aims to reveal the underlying molecular mechanisms responsible for the antioxidative action of EA. For this purpose, its reactions with HO• and CCl3OO• radicals were simulated at physiological conditions using the quantum mechanics-based test for overall free-radical scavenging activity. The density functional theory in combination with the conductor-like polarizable continuum solvation model was utilized. With HO• radical EA conforms to the hydrogen atom transfer and radical adduct formation mechanisms, whereas sequential proton loss electron transfer mechanism is responsible for scavenging of CCl3OO• radical. In addition, compared to trolox, EA was found more reactive toward HO•, but less reactive toward CCl3OO•. The calculated rate constants for the reactions of EA with both free radicals are in a very good agreement with the corresponding experimental values.

Unveiling the role of short-range exact-like exchange in the optimally tuned range-separated hybrids for fluorescence lifetime modeling.

We propose and validate several variants of the optimally tuned range-separated hybrid functionals (OT-RSHs) including different density functional approximations for predicting the fluorescence lifetimes of different categories of fluorophores within the time-dependent density functional theory (TD-DFT) framework using both the polarizable continuum and state-specific solvation models. Our main idea originates from performing the optimal tuning in the presence of a contribution of the exact-like exchange at the short-range part, which, in turn, leads to the small values of the range-separation parameter, and computing the fluorescence lifetimes using the models including no or small portions of the short-range exact-like exchange. Particular attention is also paid to the influence of the geometries of emitters on fluorescence lifetime computations. It is shown that our developed OT-RSHs along with the polarizable continuum model can be considered as the promising candidates within the TD-DFT framework for the prediction of fluorescence lifetimes for various fluorophores. We find that the proposed models not only outperform their standard counterparts but also provide reliable data better than or comparable to the conventional hybrid functionals with both the fixed and interelectronic distance-dependent exact-like exchanges. Furthermore, it is also revealed that when the excited state geometries come into play, more accurate descriptions of the fluorescence lifetimes can be achieved. Hopefully, our findings can give impetus for future developments of OT-RSHs for computational modeling of other characteristics in fluorescence spectroscopy as well as for verification of the related experimental observations.

Hydrolysis and Condensation of n-BuSnCl3: Enabling Deposition of Smooth Metal Oxide Photoresist Thin Films.

Herein, we report hydrolysis and condensation chemistries of C4H9SnCl3 to molecular clusters and gel films. Precursor speciation plays a key role in film formation and quality toward realization of atomically smooth surfaces. Density functional theory investigations of C4H9SnCl3 and its reactions show that hydrolysis of the dimer (C4H9Sn)2(OH)2Cl4(H2O)2 has a high energetic penalty in the gas phase and when using a polarizable continuum solvation model based on density. These computations support our observed stability of the dimeric cluster in air, in various solvents, and through initial film deposition. It hydrolyzes and condenses to the [(C4H9Sn)12O14(OH)6]2+ dodecamer on-chip after a post film-deposition bake at 80 °C. Consequently, film surface smoothness is uniquely retained through on-wafer condensation.

Ab Initio Molecular Dynamics Investigation of Beryllium Complexes.

Structures of aqueous [Be(H2O)4]2+, its outer-sphere and inner-sphere complexes with F-, Cl-, and SO42-, and dinuclear complexes with a [Be2(κ-OH)(κ-SO4)]+ core have been studied through Car-Parrinello molecular dynamics (CPMD) simulations with the BLYP functional. According to constrained CPMD/BLYP simulations and pointwise thermodynamic integration, the free energy of deprotonation of [Be(H2O)4]2+ and its binding free energy with F- are 9.6 and -6.2 kcal/mol, respectively, in good accord with available experimental data. The computed activation barriers for replacing a water ligand in [Be(H2O)4]2+ with F- and SO42-, 10.9 and 13.6 kcal/mol, respectively, are also in good qualitative agreement with available experimental data. These ligand-substitution reactions are indicated to follow associative interchange mechanisms with backside (SN2-like) attack of the anion relative to the aquo ligand it is displacing. Outperforming static density functional theory computations of the salient kinetic and thermodynamic quantities involving simple polarizable continuum solvent models, CPMD simulations are validated as a promising tool for studying the structures and speciation of beryllium complexes in aqueous solution.

On the physical-chemical nature of solvent polarizability and dipolarity.

The positive solvatochromism of three dyes, with a spectral behavior strongly dependents on the medium dipolarity/polarizability, was studied theoretically. Both a polarizable continuum-solvent model (CSM) and explicit solvent molecules were employed to model solvent effects. The CSM approach, coupled with ten different TDDFT methods, yielded unsatisfactory results in eleven solvents. The explicit-solvation calculations, thought of much higher computational cost, yielded excellent results. As CSM schemes are known correctly model non-specific electrostatic effects, our results indicate that the traditionally considered non-specific nature of solvent dipolarity needs to be reconsidered, requiring the explicit consideration of the solute-solvent interactions for their accurate theoretical description.

CCSD‐PCM Excited State Energy Gradients with the Linear Response Singles Approximation to Study the Photochemistry of Molecules in Solution

AbstractWe present the theory and the implementation for the excited state energy gradients with respect to nuclear displacements for the linear response coupled cluster with single and double excitations (LR‐CCSD) combined with the polarizable continuum model of solvation within the LR formalism and the singles approximation (LR‐PCM‐PTES). This approach allows the exploration of the excited state potential energy surface of solvated molecules for the evaluation of minima and other stationary points, at a computational cost virtually identical to that of gas‐phase LR‐CCSD. The method is applied to the evaluation of vertical absorption and emission energies of 4‐(N,N)‐dimethyl‐aminobenzonitrile (DMABN) in gas phase, cyclohexane, and acetonitrile solutions. The method is able to find the minima for the locally excited and charge transfer states, which are responsible for the dual‐fluorescence of this compound. At the same time, some limitations of the LR and state specific (SS) formalisms for excited state solvation, which suffer from under or overestimation of the solvent effect in excited states, are discussed.

PF5 and PCl5 interacting with water – Comparative study at the molecular level

The isomeric structures formed by the interaction of PF5 and PCl5 with up to four water molecules were theoretically examined by employing the MP2 method and the aug-cc-pVDZ basis set. The additional effects of surrounding water molecules were approximated by employing the polarized continuum solvation model (PCM) within a self-consistent reaction field treatment. The calculations indicate that the global minimum resulting from the interaction of PF5 and one H2O molecule corresponds to the PF5–H2O adduct and remains the most stable isomer after addition of second and third H2O, whereas the presence of fourth H2O molecule renders the PF5OH−/H3O+/2H2O structure the most stable. On the contrary, the interaction of PCl5 and a single H2O molecule leads to the global minimum structure corresponding to the PCl3O phosphoryl chloride with two HCl moieties attached. The lowest energy isomers resulting from the interaction of PCl5 with two, three, and four H2O molecules indicate the tendency of PCl3O to subsequent replacement of the Cl ligands with OH groups resulting in formation of H3PO4 (with five surrounding HCl fragments) when the number of available H2O molecules is sufficient. The presence of the competitive isomers containing H3O+ fragments in the case of the PCl5 interacting with water molecules is also predicted and discussed.

Improving Performance of the SMD Solvation Model: Bondi Radii Improve Predicted Aqueous Solvation Free Energies of Ions and pKa Values of Thiols

Calculation of the solvation free energy of ionic molecules is the principal source of errors in the quantum chemical evaluation of pKa values using implicit polarizable continuum solvent models. One of the important parameters affecting the performance of these models is the choice of atomic radii. Here, we assess the performance of the solvation model based on density (SMD) implicit solvation model employing SMD default radii (SMD) and Bondi radii (SMD-B), a set of empirical atomic radii developed based on the crystallographic data. For a set of 112 ions (60 anions and 52 cations), the SMD-B model showed lower mean unsigned error (MUE) for predicted aqueous solvation free energies (4.0 kcal/mol for anions and 2.4 kcal/mol for cations) compared to the standard SMD model (MUE of 5.0 kcal/mol for anions and 2.9 kcal/mol for cations). In particular, usage of Bondi radii improves the aqueous solvation energies of sulfur-containing ions by >5 kcal/mol compared to the SMD default radii. Indeed, for a set of 45 thiols, the SMD-B model was found to dramatically improve the predicted pKa values, with ∼1 pKa unit mean deviation from the experimental values, compared to ∼7 pKa units mean deviation for the SMD model with the default radii. These findings highlight the importance of the choice of atomic radii on the performance of the implicit solvation models.

The mechanisms of isobutene hydration yielding tert-butanol catalyzed by a strong mineral acid (H2SO4) and Lewis-Brønsted superacid (HF/SbF5)

The mechanism of the (CH3)2CCH2+H2O→(CH3)3COH reaction catalyzed by two strong acids (H2SO4 and HSbF6) was investigated theoretically using the ab initio MP2 and CCSD(T) methods and the aug-cc-pVDZ/LANL2DZ and aug-cc-pVTZ/LANL2DZ basis sets. The effects of surrounding solvent molecules were approximated by employing the polarized continuum solvation model. The most important findings include the observation that both acids are capable of catalyzing isobutene hydration but the reaction is predicted to proceed faster when the HSbF6 superacid plays the catalyst role.

Multithreaded parallelization of the energy and analytic gradient in the fragment molecular orbital method

AbstractThe fragment molecular orbital method in GAMESS is parallelized in a multithreaded OpenMP implementation combined with the MPI version of the two‐level generalized distributed data interface. The energy and analytic gradient in gas phase and the polarizable continuum model of solvation are parallelized in this hybrid three‐level scheme, achieving a large memory footprint reduction and a high parallel efficiency on Intel Xeon Phi processors. The parallel efficiency is demonstrated on the Stampede2 and Theta supercomputers using up to 2048 nodes (262 144 threads).

A new insight of structures, bonding and electronic properties for 6-mercaptopurine and Ag8 clusters configurations: a theoretical perspective

BackgroundMany reports have also shown that the silver nanoparticles can effectively increase the anticancer drug activity and intensely enhance the drug curative effect. The adsorption of 6MP on nanomaterials has received a lot of attentions because of the drug coordination to its chemotherapeutic activity. The geometrical structures, chemical bonds, molecular orbital properties as well as density of states for the configurations were analyzed to deeply understand the interactions between the 6MP and Ag8 clusters for high effect anticancer drug production.ResultsIn this work, the density functional theory B3LYP has been used to investigate the structures and properties of the configurations between 6-mercaptopurine (6MP) and Ag8 clusters using 6-311++G** level as well as an effective pseudo potential LANL2DZ. The geometries of ten configurations were optimized with full freedom. The geometrical structures, chemical bonds, molecular orbital properties as well as density of states for partial configurations were analyzed based on the density functional calculations. Polarizable continuum solvent model (PCM) in self-consistent reaction field (SCRF) were used for the aqueous calculations. The influences of temperature and pressure on the stability of the predominant configurations in the gas phase were further considered using standard statistical thermodynamic methods from 50 to 500 K and at 1 bar or 100 bar.ConclusionThe result shows that there are ten stable configurations in the gas phase and there is a strong chemical bond between a Ag and S atom in the most stable configuration. The analysis of density of states also shows that the Ag–S chemical bond in the most stable configuration has been formed. Moreover, the results show that the temperature and the pressure will significantly influence the stability of the configurations in the gas phase. Additionally, when the solvent effect was considered, we found that there are only seven stable configurations and the solvent have different effect on various configurations.

The Fragment Molecular Orbital Method Based on Long-Range Corrected Density-Functional Tight-Binding.

The presently available linear scaling approaches to density-functional tight-binding (DFTB) based on the fragment molecular orbital (FMO) method are severely impacted by the problem of artificial charge transfer due to the self-interaction error (SIE), which hampers the simulation of zwitterionic systems such as biopolymers or ionic liquids. Here we report an extension of FMO-DFTB where we included a long-range corrected (LC) functional designed to mitigate the DFTB SIE, called the FMO-LC-DFTB method, resulting in a robust method which succeeds in simulating zwitterionic systems. Both energy and analytic gradient are developed for the gas phase and the polarizable continuum model of solvation. The scaling of FMO-LC-DFTB with system size N is shown to be almost linear, O( N1.13-1.28), and its numerical accuracy is established for a variety of representative systems including neutral and charged polypeptides. It is shown that pair interaction energies between fragments for two mini-proteins are in excellent agreement with results from long-range corrected density functional theory. The new method was employed in long time scale (1 ns) molecular dynamics simulations of the tryptophan cage protein (PDB: 1L2Y ) in the gas phase for four different protonation states and in stochastic global minimum structure searches for 1-ethyl-3-methylimidazolium nitrate ionic liquid clusters containing up to 2300 atoms.

Evaluation of DFT Methods and Implicit Solvation Models for Anion‐Binding Host‐Guest Systems

AbstractAlthough supramolecular chemistry is traditionally an experimental discipline, computations have emerged as important tools for the understanding of supramolecules. We have explored how well commonly used density functional theory quantum mechanics and polarizable continuum solvation models can calculate binding affinities of host‐guest systems. We report the calculation of binding affinities for eight host–guest complexes and compare our results to experimentally measured binding free energies that span the range from −2.3 to −6.1 kcal mol−1. These systems consist of four hosts (biotin[6]uril, triphenoxymethane, cryptand, and bis‐thiourea) with different halide ions (F−, Cl−, Br−) in various media including organic and aqueous. The mean average deviation (MAD) of calculated from measured ΔGa is 2.5 kcal mol−1 when using B3LYP‐D3 with either CPCM or PCM. This MAD value lowers even more by eliminating two outliers: 1.1 kcal mol−1 for CPCM and 1.2 kcal mol−1 for PCM. The best DFT and implicit solvation model combination that we have studied is B3LYP−D3 with either CPCM or PCM.

Quantum chemical calculations of hydration electrostatics and electrochemical oxidation potential of cyclic nitroxide radicals

The oxidation potential Eox of cyclic nitroxide radicals in water has been calculated using density functional theory methods and the polarizable continuum solvent model. Robust correlations were obtained between the calculated and experimental Eox values with the lowest mean unsigned error of 10 mV. The electrostatic model was demonstrated as a useful approximation for the calculations of Eox.

Probing deoxysugar conformational preference: A comprehensive computational study investigating the effects of deoxygenation

Deoxysugars are intrinsic components in a number of antibiotics, antimicrobials, and therapeutic agents that often dictate receptor binding, improve efficacy, and provide a diverse toolbox in modifying glycoconjugate function due to an extensive number of unique isomers and inherent conformational flexibility. Hence, this work provides a comprehensive examination of the conformational effects associated with deoxygenation of the pyranose ring. Both the location and degree of deoxygenation were evaluated by interrogating the energetic landscape for a number of mono- and dideoxyhexopyranose derivatives using DFT methods (M05-2X/cc-pVTZ(-f)). Both anomeric forms and in some cases, the alternate chair form, have been investigated in the gas phase. As was documented in a preceding study, variation of the C-6 oxidation state has been shown to affect the anomeric preference of select glucose stereoisomers. Similar results were also observed for several deoxysugar isomers in this work, wherein the alternate anomer was favored upon reduction to the 6-deoxyhexose derivative or oxidation to the hexonic acid. Additionally, comparison of relative Gibbs free energies revealed C-3 deoxygenation imparts greater instability compared to C-2 or C-4 deoxygenation, as indicated by an increase in free energy for 3-deoxysugars. A polarizable continuum solvation model was also applied to empirically validate theoretical results for several deoxysugars, wherein good agreement with both carbon (σ = 1.6 ppm) and proton (σ = 0.20 ppm) NMR shifts was observed for the majority of isomers. Solvated and gas phase anomeric ratios were also calculated and compared favorably to reported literature values, although some discrepancies are noted.

The importance of specific solvent–solute interactions for studying UV–vis spectra of light-responsive molecular switches

Short-range interactions between solvents and molecular switches influence their structure, electronic transitions, and stability. The explicit solvent interactions between water and N ′-[1-(2-hydroxyphenyl)ethyliden]isonicotinoyl hydrazone, as a representative of the light-responsive molecule, were investigated by quantum chemical techniques, density functional theory, natural bond orbital, and quantum theory of atoms in molecules. On the basis of the preliminary spectra obtained with the polarizable continuum solvent model, the most probable groups for the formation of specific interactions were determined. The experimental UV-vis spectrum was reproduced with the addition of five molecules of water and interactions between solvent and solute are discussed in detail. The number of water molecules was reduced to one and it was proven that this can be sufficient for the reproduction of the experimental spectra if solvent molecules are placed in the right position. Quantum theory of atoms in molecules analysis gave better insight into the change of bond critical point parameters with distance, especially for the formed hydrogen bonds.

Mechanism of the ethanol-based (C2H5OH2)+(SbF6)− salt formation by the superacid-catalyzed acetaldehyde hydrogenation

The mechanism of the acetaldehyde hydrogenation reaction yielding the ethanol-based (C2H5OH2)+(SbF6)− salt with the assistance of the HSbF6 (HF/SbF5) superacid catalyst was investigated theoretically using ab initio MP2 and CCSD(T) methods and the aug-cc-pVDZ basis set. (The effects of surrounding solvent were approximated by employing the polarized continuum solvation model and by the explicit inclusion of one solvent molecule.) The most important findings include the observation that the activation barriers calculated for both phases considered are significantly reduced (by 66%) in comparison with the uncatalyzed acetaldehyde hydrogenation process. The reaction begins with the spontaneous (barrier-less) protonation of acetaldehyde by the superacid and continues through the formation of ethanol molecule followed by its subsequent protonation by the recovered HSbF6. The overall process is exoenergetic by 63 kcal/mol and leads to the formation of the ethanol-based (C2H5OH2)+(SbF6)− ionic salt as the final product.

Coupled cluster theory with the polarizable continuum model of solvation

AbstractThe environment may significantly affect molecular properties. Thus, it is desirable to account explicitly for these effects on the wave function and its derivatives, especially when the latter are evaluated with accurate methods, such as those belonging to coupled cluster (CC) theory. In this tutorial review, we discuss how to combine CC methods with the polarizable continuum model of solvation (PCM). We describe useful approximations that include the solvent response to the correlation and excited state equations while maintaining the computational cost comparable to in vacuo calculations. Although applied to PCM, the theoretical framework presented in this review is general and can be used with any polarizable embedding model. Representative applications of the CC‐PCM method to ground and excited state properties of solvated molecules are presented, and comparisons with experiment, and between the full and approximate schemes are discussed.