Polarizable Continuum Solvation Model Research Articles

Comparison of the Marcus and Pekar partitions in the context of non-equilibrium, polarizable-continuum solvation models.

The Marcus and Pekar partitions are common, alternative models to describe the non-equilibrium dielectric polarization response that accompanies instantaneous perturbation of a solute embedded in a dielectric continuum. Examples of such a perturbation include vertical electronic excitation and vertical ionization of a solution-phase molecule. Here, we provide a general derivation of the accompanying polarization response, for a quantum-mechanical solute described within the framework of a polarizable continuum model (PCM) of electrostatic solvation. Although the non-equilibrium free energy is formally equivalent within the two partitions, albeit partitioned differently into "fast" versus "slow" polarization contributions, discretization of the PCM integral equations fails to preserve certain symmetries contained in these equations (except in the case of the conductor-like models or when the solute cavity is spherical), leading to alternative, non-equivalent matrix equations. Unlike the total equilibrium solvation energy, however, which can differ dramatically between different formulations, we demonstrate that the equivalence of the Marcus and Pekar partitions for the non-equilibrium solvation correction is preserved to high accuracy. Differences in vertical excitation and ionization energies are <0.2 eV (and often <0.01 eV), even for systems specifically selected to afford a large polarization response. Numerical results therefore support the interchangeability of the Marcus and Pekar partitions, but also caution against relying too much on the fast PCM charges for interpretive value, as these charges differ greatly between the two partitions, especially in polar solvents.

Vibrational Properties of the Phosphate Group Investigated by Molecular Dynamics and Density Functional Theory.

The phosphate group (PO2(-)) is an important building block occurring in many components of living matter including nucleic acids. It provides distinct features in vibrational spectra and is useful as a local probe of NA conformation and interactions with the environment. For this purpose, it is desirable to explore in detail various factors influencing spectral shapes of characteristic phosphate vibrations. In the present study, effects of the solvent and conformational averaging are analyzed for simple model molecules, dimethylphosphate, ethylmethylphosphate, and ethylmethylthiophosphate. Infrared absorption (IR) and Raman spectra were measured and calculated using a combination of molecular dynamics (MD) and density functional theory (DFT). To fully understand the link between the structure and the spectra, the solvent has to be explicitly included in the computational modeling. The results indicate that vibrational properties of the phosphate moiety are very sensitive to its conformation and interactions with the aqueous environment indeed. Polarizable continuum solvent models without explicit water molecules provided significantly worse agreement with the experiment. The combined MD/DFT approach captures well spectral characteristics for the model systems and constitutes the most reliable basis for exploration of phosphate vibrational properties in biomolecular structural studies.

MP2 calculation of (77) Se NMR chemical shifts taking into account relativistic corrections.

The main factors affecting the accuracy and computational cost of the Second-order Möller-Plesset perturbation theory (MP2) calculation of (77) Se NMR chemical shifts (methods and basis sets, relativistic corrections, and solvent effects) are addressed with a special emphasis on relativistic effects. For the latter, paramagnetic contribution (390-466 ppm) dominates over diamagnetic term (192-198 ppm) resulting in a total shielding relativistic correction of about 230-260 ppm (some 15% of the total values of selenium absolute shielding constants). Diamagnetic term is practically constant, while paramagnetic contribution spans over 70-80 ppm. In the (77) Se NMR chemical shifts scale, relativistic corrections are about 20-30 ppm (some 5% of the total values of selenium chemical shifts). Solvent effects evaluated within the polarizable continuum solvation model are of the same order of magnitude as relativistic corrections (about 5%). For the practical calculations of (77) Se NMR chemical shifts of the medium-sized organoselenium compounds, the most efficient computational protocols employing relativistic Dyall's basis sets and taking into account relativistic and solvent corrections are suggested. The best result is characterized by a mean absolute error of 17 ppm for the span of (77) Se NMR chemical shifts reaching 2500 ppm resulting in a mean absolute percentage error of 0.7%.

Conformational landscape and low lying excited states of imatinib.

The conformational changes of imatinib (IMT) are crucial for understanding the ligand-receptor interaction and its mechanism of action [Agofonov et al. (2014) Nature Struct Mol Biol 21:848-853]. Therefore, here we investigated the free energy conformational landscape of the free IMT base, aiming to describe the three-dimensional structures and energetic stability of its conformers. Forty-five unique conformers, within an energy window of 4.8kcalmol(-1) were identified by a conformational search in gas-phase, at the B3LYP/6-31G(d) theoretical level. Among these, the 20 most stable, as well as 4 conformers resulting from optimization of experimental structures found in the two known polymorphs of IMT and in the c-Abl complex were further refined using the 6-31+G(d,p) basis set and the polarizable continuum solvation model. The most stable conformers in gas-phase and water exhibit a V-shaped structure. The major difference between the most stable free conformers and the bioactive conformers consists in the relative orientation of the pyrimidine-pyridine groups responsible for hydrogen bonding interactions in the ATP-binding pocket. The ratio of mole fractions corresponding to the two known (α and β) polymorphic forms of IMT was estimated from the calculated thermochemical data, in quantitative agreement with the existing experimental data related to their solubility. The electronic absorption spectrum of this compound was investigated in water and explained based on the theoretical TD-DFT results, considering the Boltzmann population-averaged computed data at CAM-B3LYP/6-31+G(d,p) level of theory for the nine most stable conformers.

Modeling photoionization of aqueous DNA and its components.

Radiation damage to DNA is usually considered in terms of UVA and UVB radiation. These ultraviolet rays, which are part of the solar spectrum, can indeed cause chemical lesions in DNA, triggered by photoexcitation particularly in the UVB range. Damage can, however, be also caused by higher energy radiation, which can ionize directly the DNA or its immediate surroundings, leading to indirect damage. Thanks to absorption in the atmosphere, the intensity of such ionizing radiation is negligible in the solar spectrum at the surface of Earth. Nevertheless, such an ionizing scenario can become dangerously plausible for astronauts or flight personnel, as well as for persons present at nuclear power plant accidents. On the beneficial side, ionizing radiation is employed as means for destroying the DNA of cancer cells during radiation therapy. Quantitative information about ionization of DNA and its components is important not only for DNA radiation damage, but also for understanding redox properties of DNA in redox sensing or labeling, as well as charge migration along the double helix in nanoelectronics applications. Until recently, the vast majority of experimental and computational data on DNA ionization was pertinent to its components in the gas phase, which is far from its native aqueous environment. The situation has, however, changed for the better due to the advent of photoelectron spectroscopy in liquid microjets and its most recent application to photoionization of aqueous nucleosides, nucleotides, and larger DNA fragments. Here, we present a consistent and efficient computational methodology, which allows to accurately evaluate ionization energies and model photoelectron spectra of aqueous DNA and its individual components. After careful benchmarking, the method based on density functional theory and its time-dependent variant with properly chosen hybrid functionals and polarizable continuum solvent model provides ionization energies with accuracy of 0.2-0.3 eV, allowing for faithful modeling and interpretation of DNA photoionization. The key finding is that the aqueous medium is remarkably efficient in screening the interactions within DNA such that, unlike in the gas phase, ionization of a base, nucleoside, or nucleotide depends only very weakly on the particular DNA context. An exception is the electronic interaction between neighboring bases which can lead to sequence-specific effects, such as a partial delocalization of the cationic hole upon ionization enabled by presence of adjacent bases of the same type.

Substituent effect on the proton-related phenomena and chelation behavior of hydroxypicolinic compounds: a DFT investigation

Comparative study on kinetics and thermodynamics of proton-related reactions of hydroxypicolinic acids has been carried out using density functional theory associated with polarizable continuum model of solvation. Mechanisms for such reactions have been established. Both 3- and 4-hydroxypicolinic acid prefer zwitterionic forms to normal forms. For 6-hydroxypicolinic acid, keto forms are highly preferred. The pK a values and UV/Vis bands predicted for some picolinic compounds agree with the experiment. 5-Hydroxypicolinate shows the highest preference for complexation with copper(II) but 6-hydroxypolinate gives rise to the most stable complex. Kinetic stability of the trans-isomer relative to the cis-isomer of the complexes has been evaluated. UV/Vis spectral data predicted for some picolinate complexes are also in agreement with the previous experiment.

Computational biotransformation profile of paracetamol catalyzed by cytochrome P450.

The P450-catalyzed biotransformation of the analgesic drug paracetamol (PAR) is a long-debated topic, involving different mechanistic hypotheses as well as experimental evidence for the metabolites N-acetyl-p-benzoquinone imine (NAPQI), p-benzoquinone, acetamide, and 3-hydroxy-PAR. During the catalytic cycle of P450, a high-valent iron(IV)-oxo species known as Compound I (Cpd I) is formed as the ultimate oxidant, featuring two energetically close-lying ground states in the doublet (low-spin) and quartet (high-spin) spin states, respectively. In order to clarify the catalytic mechanism, a computational chemistry analysis has been undertaken for both the high- and low-spin routes, employing density functional theory (DFT) including PCM (polarized continuum-solvation model) that yields an approximate simulation of the bulk polarization exerted through the protein. The results demonstrate that hydrogen abstraction transfer (HAT) by the P450 oxidant Cpd I (FeO) is kinetically strongly preferred over the alternative pathways of an oxygen addition reaction (OAR) or two consecutive single-electron transfers (SET). Moreover, only the respective high-spin route yields N-acetyl-p-semiquinone imine (NAPSQI) as an intermediate that is converted to the electrophile N-acetyl-p-benzoquinone imine (NAPQI). By contrast, 3-hydroxy-PAR, acetamide, and p-benzoquinone as electrophilic and redox-active agent are formed predominantly in the low-spin state through reactions that do not involve NAPSQI. Thus, all experimentally observed PAR metabolites are in accord with an initial HAT from the phenolic oxygen, and NAPSQI should indeed be the precursor of NAPQI, both of which are generated only via the high-spin pathway.

Relation of molecular structure to Franck–Condon bands in the visible-light absorption spectra of symmetric cationic cyanine dyes

A Franck–Condon (FC) model is used to study the solution-phase absorbance spectra of a series of seven symmetric cyanine dyes having between 22 and 77 atoms. Electronic transition energies were obtained from routine visible-light absorbance and fluorescence emission spectra. Harmonic normal modes were computed using density functional theory (DFT) and a polarizable continuum solvent model (PCM), with frequencies corrected using measured mid-infrared spectra. The model predicts the relative energies of the two major vibronic bands to within 5% and 11%, respectively, and also reproduces structure-specific differences in vibronic band shapes. The bands themselves result from excitation of two distinct subsets of normal modes, one with frequencies between 150 and 625cm−1, and the other between 850 and 1480cm−1. Vibronic transitions excite symmetric in-plane bending of the polymethine chain, in-plane bends of the polymethine and aromatic C–H bonds, torsions and deformations of N-alkyl substituents, and in the case of the indocyanines, in-plane deformations of the indole rings. For two dyes, the model predicts vibronic coupling into symmetry-breaking torsions associated with trans–cis photoisomerization.

Quantum mechanical and molecular mechanics approach with a multilayered-quantum representation study of solvent effects and potentials of mean force for the CH3CH2Cl + ClO− SN2 reaction in aqueous solution

The bimolecular nucleophilic substitution reaction of CH3CH2Cl + ClO− in aqueous solution was investigated using a multilayered-quantum representation, quantum mechanical and molecular mechanics approach with an explicit water model. Ten configurations along the reaction pathway including reactant complex, transition state and product complex were analyzed in the presence of the aqueous solution. The obtained free energy activation barrier under the CCSD(T)/MM representation is 13.2 kcal/mol, while it is 11.7 kcal/mol under the DFT/MM representation which agrees very well with the DFT calculation, at 11.0 kcal/mol, with a polarizable continuum solvent model. The solvent effects including the solvation free energy contribution and the polarization effect raise the free activation barrier by 9.8 kcal/mol. The rate constant, at 298 K, is 5.27 × 10−17 cm3/molecule/s which is about seven orders of magnitude smaller than that in the gas phase (1.10 × 10−10 cm3/molecule/s). All in all, the aqueous solution plays an essential role in shaping the reaction pathway for this reaction in water.

Theoretical investigation on SnCl4-catalyzed tandem dimerization/oxy-2-azonia-Cope rearrangements between β,γ-unsaturated ketones and imines

The mechanism of the Lewis acid-catalyzed oxy-2-azonia-Cope rearrangement between β,γ-unsaturated ketones and imines leading to the formation of homoallylic amides and lactams has been theoretically studied using the B3LYP density functional theory methods enhanced with a polarized continuum solvation model. It was predicted that the SnCl 4 -catalyzed tandem dimerization/oxy-2-azonia- Cope rearrangement mechanism is highly preferred over the uncatalyzed version as well as the plausible tandem dimerization/Prins rearrangement mechanism. A two-step pathway was found for the overall reaction, involving the initial nucleophilic dimerization followed by the (3,3)-sig- matropic rearrangement. The latter phase was considered to be the rate-limiting step. Particularly, the transition states account for the experimentally observed stereoselectivities and Z/E selectivities. The high stereoselectivity and Z/E selectivity for the chiral cyclic substrates can be attributed to the relative conformational stabilities of TSs. Moreover, distortion-interaction analysis has been performed in an attempt to quantify the various contributions to the reac- tion transition states, and it revealed that interaction energy E II and distortion energy ∆Ed associated with the forma- tion of the 2COM2 complex are the determining factors to

Medium Effect on Solvation Free Energy, Dipole Moment and Molecular Reactivity of Naproxen

In this paper, a computational study of medium effect on solvation free energy, dipole moment and different molecular properties like global reactivity descriptors (chemical hardness, softness, chemical potential, electronegativity, electrophilicity index) of naproxen have been reported. Hartee–Fock (HF) and Becke, 3-parameter, Lee-Yang-Parr (B3LYP) level of theory with 6-31G(d) and 6-31G(d,p) basis sets were applied for gas phase and solution. The solvation free energy, dipole moment and molecular properties were calculated by employing two solvation models namely polarizable continuum model (PCM) and Solvation Model on Density (SMD). For all levels of theory, the solvation free energies were gradually increased in going from lower to higher dielectric constant for PCM, but opposite result was observed in case of SMD model. However, with SMD, the solvation free energies were higher than that of PCM in all the solvent systems. The dipole moment of naproxen was found to be increased when going from non-polar to polar solvents for both PCM and SMD model. The dipole moment of naproxen was higher in different solvents than that of the gas phase. Moreover, Ongoing from non-polar to polar solvent the chemical potential, electronegativity and electrophilicity index were increased regardless of the solvation models, basis sets and level of theories used. On the other hand, no noticeable medium effect was observed on chemical hardness and softness. The results obtained in this study may lead to understand the stability and reactivity of naproxen and the results will be of assistance to use the title molecule in reaction intermediates and pharmaceuticals.

A comprehensive study of the solvent effects on the cycloaddition reaction of diethyl azodicarboxylate and ethyl vinyl ether: Efficient implementation of QM and TD-DFT study

In this work, quantum chemistry calculations performed to study the kinetics and thermodynamic parameters of [2+2] cycloaddition reaction of diethyl azodicarboxylate and ethyl vinyl ether in eighty-three solvents and gas phase. The solvent effect on the reaction path and electron density of the C2N6 critical bond as the reaction coordinate at the TS was investigated. Calculated rate constants in various solvents showed that increase in the activation dipole moment accelerates the reaction. Based on the time-dependent studies, using a conductor like polarizable continuum model solvation model, the solvent effects on the excitation energies of the reactants and transition states (TSs) and the corresponding chemical shifts were analyzed. Finally, some correlations between the rate constant and quantum reactivity indices such as electrophilicity index, chemical hardness, and electronic chemical potential were investigated. © 2014 Wiley Periodicals, Inc.

Four-component relativistic calculations in solution with the polarizable continuum model of solvation: theory, implementation, and application to the group 16 dihydrides H2X (X = O, S, Se, Te, Po).

We present a formulation of four-component relativistic self-consistent field (SCF) theory for a molecular solute described within the framework of the polarizable continuum model (PCM) for solvation. The linear response function for a four-component PCM-SCF state is also derived, as well as the explicit form of the additional contributions to the first-order response equations. The implementation of such a four-component PCM-SCF model, as carried out in a development version of the DIRAC program package, is documented. In particular, we present the newly developed application programming interface PCMSolver used in the actual implementation with DIRAC. To demonstrate the applicability of the approach, we present and analyze calculations of solvation effects on the geometries, electric dipole moments, and static electric dipole polarizabilities for the group 16 dihydrides H2X (X = O, S, Se, Te, Po).

Uranyl solvation by a reference interaction site model

We apply the one-dimensional reference interaction site model (RISM) to the solvation of uranyl in water. Uranyl aqua complexes with 4–6 explicit water ligands and an implicit water solvent, modeled by RISM to represent the further solvent environment, have been examined. The interaction of explicitly represented atoms of the aqua complexes are treated either by molecular mechanics or density functional theory, to build the free energy functional. A comparison of solvation energies and geometries of the aqua complexes for different numbers of explicit water ligands at the local minimum of the free energy surface indicate the interchangeability of explicit and implicit solvent models. Consequently the solvation energy is rather independent of the number of aqua ligands of the uranyl complex used as solute model, in contrast to results of a polarizable continuum model of solvation. For uranyl with four and five explicit water ligands in the first solvation shell we determined only a minor preference for the latter, in agreement with experiment. Other computational approaches tend to overestimate this preference.

Solvent induced conformational fluctuation of alanine dipeptide studied by using vibrational probes

The solvation effect on the three dimensional structure and the vibrational feature of alanine dipeptide (ALAD) was evaluated by applying the implicit solvents from polarizable continuum solvent model (PCM) through ab initio calculations, by using molecular dynamic (MD) simulations with explicit solvents, and by combining these two approaches. The implicit solvent induced potential energy fluctuations of ALAD in CHCl3, DMSO and H2O are revealed by means of ab initio calculations, and a global view of conformational and solvation environmental dependence of amide I frequencies is achieved. The results from MD simulations with explicit solvents show that ALAD trends to form PPII, αL, αR, and C5 in water, PPII and C5 in DMSO, and C5 in CHCl3, ordered by population, and the demonstration of the solvated structure, the solute–solvent interaction and hydrogen bonding is therefore enhanced. Representative ALAD–solvent clusters were sampled from MD trajectories and undergone ab initio calculations. The explicit solvents reveal the hydrogen bonding between ALAD and solvents, and the correlation between amide I frequencies and the CO bond length is built. The implicit solvents applied to the ALAD–solvent clusters further compensate the solvation effect from the bulk, and thus enlarge the degree of structural distortion and the amide I frequency red shift. The combination of explicit solvent in the first hydration shell and implicit solvent in the bulk is helpful for our understanding about the conformational fluctuation of solvated polypeptides through vibrational probes.

Quantum chemical and steered molecular dynamics studies for one pot solution to reactivate aged acetylcholinesterase with alkylator oxime

Dimethyl(pyridin-2-yl)sulfonium based oxime has been designed to reverse the aging process of organophosphorus inhibited AChE and to reactivate the aged-AChE adduct. We have employed DFT M05-2X/6-31G∗ level of theory in aqueous phase with polarizable continuum solvation model (PCM) for the methylation of phosphonate ester monoanion of the soman-aged adduct. The calculated free energy of activation for the methyl transfer process from designed dimethyl(phenyl)sulfonium (1) to aged AChE–OP adduct occurs with a barrier of 31.4kcal/mol at M05-2X/6-31G∗ level of theory, which is 6.4kcal/mol lower compared to the aging process signifies the preferential reversal process to recover the aged AChE–OP adduct. The pyridine ring containing alkylated sulfonium species, dimethyl(pyridin-2-yl)sulfonium (2), reduced the free energy of activation by 4.4kcal/mol compared to the previously reported alkylating agent N-methyl-2-methoxypyridinium species (A) for the alkylation of aged AChE–OP adduct. The free enzyme can be liberated from the inhibited acetylcholinesterase with the sulfonium compound decorated with an oxime group to avoid the administration of oxime drugs separately. The calculated potential energy surfaces show that the oxime based sulfonium compound (3) can effectively methylate the aged phosphonate ester monoanion of soman aged-adduct. The calculated global reactivity descriptors of the oxime 3 also shed light on this observation. To gain better understanding for protein drug interaction as well as the unbinding and conformational changes of the drug candidate in the active site of cholinesterase, steered molecular dynamics (SMD) simulation with 3 has been performed. Through a protein–drug interaction parameters (rupture force profiles, hydrogen bonds, hydrophobic interactions), geometrical and the orientation of drug-like candidate, the oxime 3 suggests to orchestrate the better reactivation process. The docking studies have been performed with 3 in the aged AChE and BChE to obtain the initial geometry of the SMD studies. The docking methods adopted in this study have been verified with the available crystal geometry of 1-methyl-2-(pentafluorobenzyloxyimino)pyridinium compound in aged soman inhibited human BChE (PDB code: 4B0P). The computational study suggests that the newly designed oxime is a potential candidate to reactivate the aged-AChE adduct.

Polarizable continuum model solvation analysis of certain 5-substituted isoquinoline derivatives

The polarizable continuum model (PCM) analysis has been carried out using the B3LYP method with 6-311++G(d,p) basis set for 5-bromoisoquinoline (5-BIQ), 5-aminoisoquinoline (5-AIQ), 5-nitroisoquinoline (5-NIQ), 5-methylisoquinoline (5-MIQ), 5-chloroisoquinoline (5-CIQ) and 5-methoxyisoquinoline (5-MXIQ) in ten solvents with a wide range of dielectric constants. In this paper, we report electrostatic, dispersion and repulsive interaction components of Gibb's free energy of solvation along with cavitation energies for these six systems. The induced dipole moments of these six compounds in ten solvents are calculated for the three solutes. The interaction energies of the systems are discussed in terms of dielectric constant, index of refraction and surface tension of the solvents. The influence of substituent at 5-position of isoquinoline molecule on the solubility property is investigated.

Towards the versatile DFT and MP2 computational schemes for 31P NMR chemical shifts taking into account relativistic corrections.

The main factors affecting the accuracy and computational cost of the calculation of (31)P NMR chemical shifts in the representative series of organophosphorous compounds are examined at the density functional theory (DFT) and second-order Møller-Plesset perturbation theory (MP2) levels. At the DFT level, the best functionals for the calculation of (31)P NMR chemical shifts are those of Keal and Tozer, KT2 and KT3. Both at the DFT and MP2 levels, the most reliable basis sets are those of Jensen, pcS-2 or larger, and those of Pople, 6-311G(d,p) or larger. The reliable basis sets of Dunning's family are those of at least penta-zeta quality that precludes their practical consideration. An encouraging finding is that basically, the locally dense basis set approach resulting in a dramatic decrease in computational cost is justified in the calculation of (31)P NMR chemical shifts within the 1-2-ppm error. Relativistic corrections to (31)P NMR absolute shielding constants are of major importance reaching about 20-30 ppm (ca 7%) improving (not worsening!) the agreement of calculation with experiment. Further better agreement with the experiment by 1-2 ppm can be obtained by taking into account solvent effects within the integral equation formalism polarizable continuum model solvation scheme. We recommend the GIAO-DFT-KT2/pcS-3//pcS-2 scheme with relativistic corrections and solvent effects taken into account as the most versatile computational scheme for the calculation of (31)P NMR chemical shifts characterized by a mean absolute error of ca 9 ppm in the range of 550 ppm.

Can hydroxylamine be a more potent nucleophile for the reactivation of tabun-inhibited AChE than prototype oxime drugs? An answer derived from quantum chemical and steered molecular dynamics studies.

Organophosphorus nerve agents are highly toxic compounds which strongly inhibit acetylcholinesterase (AChE) in the blood and in the central nervous system (CNS). Tabun is one of the highly toxic organophosphorus (OP) compounds and is resistant to many oxime drugs formulated for the reactivation of AChE. The reactivation mechanism of tabun-conjugated AChE with various drugs has been examined with density functional theory and ab initio quantum chemical calculations. The presence of a lone-pair located on the amidic group resists the nucleophilic attack at the phosphorus center of the tabun-conjugated AChE. We have shown that the newly designed drug candidate N-(pyridin-2-yl)hydroxylamine, at the MP2/6-31+G*//M05-2X/6-31G* level in the aqueous phase with the polarizable continuum solvation model (PCM), is more effective in reactivating the tabun-conjugated AChE than typical oxime drugs. The rate determining activation barrier with N-(pyridin-2-yl)hydroxylamine was found to be ∼1.7 kcal mol(-1), which is 7.2 kcal mol(-1) lower than the charged oxime trimedoxime (one of the most efficient reactivators in tabun poisonings). The greater nucleophilicity index (ω(-)) and higher CHelpG charge of pyridinylhydroxylamine compared to TMB4 support this observation. Furthermore, we have also examined the reactivation process of tabun-inhibited AChE with some other bis-quaternary oxime drug candidates such as methoxime (MMB4) and obidoxime. The docking analysis suggests that charged bis-quaternary pyridinium oximes have greater binding affinity inside the active-site gorge of AChE compared to the neutral pyridinylhydroxylamine. The peripheral ligand attached to the neutral pyridinylhydroxylamine enhanced the binding with the aromatic residues in the active-site gorge of AChE through effective π-π interactions. Steered molecular dynamics (SMD) simulations have also been performed with the charged oxime (TMB4) and the neutral hydroxylamine. From protein-drug interaction parameters (rupture force profiles, hydrogen bonds, hydrophobic interactions), geometry and the orientation of the drug candidates, the hydroxylamine is suggested to orchestrate the reactivation process better than TMB4. Furthermore, the calculated log P values show the effective penetration of the neutral drug candidate through the blood-brain barrier. The toxicity measurements and the IC50 values (a measure of the intrinsic affinity toward AChE) suggest that the pyridinylhydroxylamine compound could have similar toxic behavior compared to the prototype oxime antidotes used for reactivation purposes. The newly designed pyridinylhydroxylamine drug candidate can be an effective antidote both kinetically and structurally to reactivate the tabun-inhibited enzyme.

The cavity electromagnetic field within the polarizable continuum model of solvation.

Cavity field effects can be defined as the consequences of the solvent polarization induced by the probing electromagnetic field upon spectroscopies of molecules in solution, and enter in the definitions of solute response properties. The polarizable continuum model of solvation (PCM) has been extended in the past years to address the cavity-field issue through the definition of an effective dipole moment that couples to the external electromagnetic field. We present here a rigorous derivation of such cavity-field treatment within the PCM starting from the general radiation-matter Hamiltonian within inhomogeneous dielectrics and recasting the interaction term to a dipolar form within the long wavelength approximation. To this aim we generalize the Göppert-Mayer and Power-Zienau-Woolley gauge transformations, usually applied in vacuo, to the case of a cavity vector potential. Our derivation also allows extending the cavity-field correction in the long-wavelength limit to the velocity gauge through the definition of an effective linear momentum operator. Furthermore, this work sets the basis for the general PCM treatment of the electromagnetic cavity field, capable to describe the radiation-matter interaction in dielectric media beyond the long-wavelength limit, providing also a tool to investigate spectroscopic properties of more complex systems such as molecules close to large nanoparticles.