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The C-1'-dithiolane Delta(8)-tetrahydrocannabinol (Delta(8)-THC) amphiphilic analogue (-)-2-(6a,7,10,10a-tetrahydro-6,6,9-trimethylhydroxy-6H-dibenzo[b,d]pyranyl)-2-hexyl-1,3-dithiolane (AMG3) is considered as one of the most potent synthetic analgesic cannabinoid (CB) ligands. Its structure is characterized by rigid tricyclic and flexible alkyl chain segments. Its conformational properties have not been fully explored. Structure-activity relationship (SAR) studies on classical CBs showed that the alkyl side chain is the most critical structural part for the receptor activation. However, reported low energy conformers of classical CB analogues vary mainly in the conformation of their alkyl side chain segment. Therefore, comparative molecular dynamics (MD) simulations of low energy conformers of AMG3 were performed in order to investigate its structural and dynamical properties in two different systems. System-I includes ligand and amphoteric solvent DMSO, simulating the biological environment and system-II includes ligand at active site of the homology models of CB1 and CB2 receptors in the solvent. The trajectory analysis results are compared for the systems I and II. In system-I, the dihedral angle defined between aromatic ring and dithiolane ring of AMG3 shows more resistance to be transformed into another torsional angle and the dihedral angle adjacent to dithiolane ring belonging in the alkyl chain has flexibility to adopt gauche+/- and trans dihedral angles. The rest of the dihedral angles within the alkyl chain are all trans. These results point out that wrapped conformations are dynamically less favored in solution than linear conformations. Two possible plane angles defined between the rigid and flexible segments are found to be the most favored and adopting values of approximately 90 degrees and approximately 140 degrees. In system-II, these values are approximately 90 degrees and approximately 120 degrees. Conformers of AMG3 at the CB1 receptor favor to establish a cis conformation defined between aromatic and dithiolane ring and a trans conformation in the CB2 receptor. These different orientations of ligand inside the binding pocket of CB1 and CB2 receptors may explain its different binding affinity in the two receptors. The results of this study can be applied to other synthetic classical CB ligands to produce low energy conformations and can be of general use for the molecules possessing flexible alkyl chain(s). In addition, this study can be useful when restraint of the alkyl chain is sought for optimizing drug design.

The linear and nonlinear optical (L&NLO) properties of the recently synthesized Xenon compounds HXeOH and HXeSH are studied. For this purpose a hierarchy of basis sets in connection with the widely used electron correlation methods, MP2, CCSD, CCSD(T), were employed in order to discuss the dipole moment, polarizability and first hyperpolarizability of these compounds. It was found that Xe insertion has a great effect on the hyperpolarizability of H2O and H2S. A significant electron correlation contribution was also observed, in particular for HXeSH. The strongly ionic character (H-Xe)+ (A-H)−, where A=O or S, of these compounds was elucitated by employing a natural bond orbital analysis. The enhanced NLO response of the studied species has been rationalized by employing a two-state model.

A great challenge toward Acquired Immunodeficiency Syndrome (AIDS) treatment is to combat the HIV-1 virus. The major problem of drug resistance has kept the virus one step ahead of the medical community, and the call for more effective drugs remains as urgent as ever. Saquinavir, the first inhibitor against HIV-1 protease, offers the most extensive clinical data regarding resistance mutations. In this work, we examine L10I, G48V, L63P, A71V, G73S, V82A, and I84V single mutant HIV-1 PR strains in complexes with saquinavir to elucidate drug-protease interactions and dynamics. A comparative analysis of these mutations at the molecular level may lead to a deeper understanding of saquinavir resistance. The G48V mutation induces structural changes to the protease that reflect upon the drug's binding affinity, as shown by MM-PBSA and thermodynamic integration (TI) calculations (ΔΔGTI = 0.3 kcal/mol; ΔΔGMM-PBSA = 1.2 kcal/mol). It was shown that mutations, which increase the flexibility of the flaps (G48V, L63P, L10I) diminish binding. The preservation of hydrogen bonds of saquinavir with both the active site and flap residues in the wild-type and certain single mutants (A71V, V82A) is also crucial for effective inhibition. It was shown that mutations conferring major resistance (G48V, L63P, I84V) did not present these interactions. Finally, it was indicated that a water-mediated hydrogen bond between saquinavir and Asp29 in the active site (wild-type, A71V, G73S) facilitates a proper placement of the drug into the binding cavity that favors binding. Mutants lacking this interaction (G48V, V82A, I84V) demonstrated reduced binding affinities. This systematic and comparative study is a contribution to the elucidation of the drug resistance mechanism in HIV-1 PR.

Human serum albumin (HSA) is the most abundant blood plasma protein, which transports fatty acids, hormones, and drugs. We consider nanoparticle-HSA interactions by investigating the binding of HSA with three fullerene analogs. Long MD simulations, quantum mechanical (fragment molecular orbital, energy decomposition analysis, atoms-in-molecules), and free energy methods elucidated the binding mechanism in these complexes. Such a systematic study is valuable due to the lack of comprehensive theoretical approaches to date. The main elements of the mechanism include the following: binding to IIA site results in allosteric modulation of the IIIA and heme binding sites with an increase in α-helical structure of IIIA. Fullerenes displayed high binding affinities for HSA; therefore, HSA can be used as a fullerene carrier, facilitating any toxic function the fullerene may exert. Complex formation is driven by hydrogen bonding, van der Waals, nonpolar, charge transfer, and dispersion energy contributions. Proper functionalization of C60 has enhanced its binding to HSA by more than an order of magnitude. This feature may be important for biological applications (e.g., photodynamic therapy of cancer). Satisfactory agreement with relevant experimental and theoretical data has been obtained.

It has been reported that beta amyloid induces production of radical oxygen species and oxidative stress in neuronal cells, which in turn upregulates β-secretase (BACE-1) expression and beta amyloid levels, thereby propagating oxidative stress and increasing neuronal injury. A series of resveratrol derivatives, known to be inhibitors of oxidative stress-induced neuronal cell death (oxytosis) were biologically evaluated against BACE-1 using homogeneous time-resolved fluorescence (TRF) assay. Correlation between oxytosis inhibitory and BACE-1 inhibitory activity of resveratrol derivatives was statistically significant, supporting the notion that BACE-1 may act as pivotal mediator of neuronal cell oxytosis. Four of the biologically evaluated resveratrol analogs demonstrated considerably higher activity than resveratrol in either assay. The discovery of some “hits” led us to initiate detailed docking studies associated with Molecular Dynamics in order to provide a plausible explanation for the experimental results and understand their molecular basis of action.

Cyclodextrins (CDs) are a well-known class of supermolecules that have been widely used to protect drugs against conjugation and metabolic inactivation as well as to enhance the aqueous solubility and hence to ameliorate the oral bioavailability of sparingly soluble drug molecules. The hepatoprotectant drug silibinin can be incorporated into CDs, and here we elucidate the interaction between the drug and the host at the molecular level. The complexation product of silibinin with 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) is characterized by Differential Scanning Calorimetry, mass spectrometry, solid and liquid high-resolution NMR spectroscopy. The chemical shift changes using (13)C CP/MAS on the complexing of the guest with the host provided significant information on the molecular interactions, and they were in agreement with the 2D NOESY results. These results point out that in both solid and liquid forms, the drug is engulfed and interacts with HP-β-CD in identical manner. Molecular dynamics calculations have been performed to examine the thermodynamic characteristics associated with the silibinin-HP-β-CD interactions and to study the stability of the complex. To approximate the physiological conditions, the aqueous solubility and dissolution characteristics of the complex at pH states simulating those of the upper gastrointestinal tract have been applied. To evaluate the antiproliferative activity of silibinin-HP-β-CD complex comparatively to silibinin in MCF-7 human cancer cells, MTT assays have been performed.

The linear and nonlinear optical properties of a series of nickel derivatives have been studied. The results have been verified and interpreted by employing a series of methods (e.g. UCCSD(T), CASSCF/CASPT2). The diradicaloid character of Ni(SCH)4 is discussred. The effect on the properties of changes in the structure of NiBDT is analysed.

This is the second part of a study to elucidate the local field effects on the nonlinear optical properties of p-nitroaniline (pNA) in three solvents of different multipolar character, that is, cyclohexane (CH), 1,4-dioxane (DI), and tetrahydrofuran (THF), employing a discrete description of the solutions. By the use of liquid structure information from molecular dynamics simulations and molecular properties computed by high-level ab initio methods, the local field and local field gradients on p-nitroaniline and the solvent molecules are computed in quadrupolar approximation. To validate the simulations and the induction model, static and dynamic (non)linear properties of the pure solvents are also computed. With the exception of the static dielectric constant of pure THF, a good agreement between computed and experimental refractive indices, dielectric constants, and third harmonic generation signals is obtained for the solvents. For the solutions, it is found that multipole moments up to two orders higher than quadrupole have a negligible influence on the local fields on pNA, if a simple distribution model is employed for the electric properties of pNA. Quadrupole effects are found to be nonnegligible in all three solvents but are especially pronounced in the 1,4-dioxane solvent, in which the local fields are similar to those in THF, although the dielectric constant of DI is 2.2 and that of the simulated THF is 5.4. The electric-field-induced second harmonic generation (EFISH) signal and the hyper-Rayleigh scattering signal of pNA in the solutions computed with the local field are in good to fair agreement with available experimental results. This confirms the effect of the "dioxane anomaly" also on nonlinear optical properties. Predictions based on an ellipsoidal Onsager model as applied by experimentalists are in very good agreement with the discrete model predictions. This is in contrast to a recent discrete reaction field calculation of pNA in 1,4-dioxane, which found that the predicted first hyperpolarizability of pNA deviated strongly from the predictions obtained using Onsager-Lorentz local field factors.

Static average polarizabilities, α, and second hyperpolarizabilities, γ, of Zn m Cd n nanoclusters for m+n=2–6 have been calculated, at the ab initio level, using effective core potentials (ECP). We have developed in a systematic way a series of basis sets. Employing a hierarchy of methods (HF, MP2, CCSD, CCSD(T)), we have computed the polarizability of Cd. The α value we computed is in excellent agreement with the best theoretical and experimental values. From the set of the designed basis sets we selected one, for the calculation of the polarizabilities of the considered clusters, which gives a satisfactory α value for Cd, at a low computational cost. The basis set for Zn has been reported in our recent study of the properties of Zn m . We have also employed the basis sets developed by Kello and Sadlej in order to compute the relativistic correction to α, which has been compared with the corresponding correlation contribution to α of Zn m Cd n . We have employed two ECPs, having a small and a large core...

The electronic and vibrational contributions to the dipole moment, polarizabilities, and first hyperpolarizabilities of HArF are reported. These have been computed by using a series of systematically built basis sets and a hierarchy of computational methods. HArF has a very large first hyperpolarizability along the z axis. This has been rationalized by invoking the difference in the electronic structure between the ground and the first excited state. The argon fluorohydride has been recently derived and characterized. The present study provides complementary data for the understanding of the electronic structure of this interesting argon derivative.

The electric field poling process of nonlinear optical chromophores embedded in an amorphous polymer matrix was studied using molecular dynamics (MD) simulations. Three systems were considered, consisting of a poly(methyl methacrylate) matrix doped with the following chromophores: N,N-dimethyl-p-nitroaniline (DPNA), 4-(dimethylamino)-4‘-nitrostilbene (DMANS), and N,N‘-di-n-propyl-2,4-dinitro-1,5-diaminobenzene (DPDNDAB). The cooling process in the presence of a poling electric field was simulated at constant NPT conditions using simulated annealing. The rotational dynamics of the dopants was investigated in the unpoled and poled states above Tg and in the poled state below Tg. The short-time behavior with respect to the back-relaxation to the unpoled state following removal of the poling field was examined for the systems below Tg and was found to deviate from the single-exponential model. The electric field effects, during and following poling, were examined by computing the angle between the dipole mom...

Density functional theory (DFT) is used to study the static electronic dipole moments, polarizabilities, polarizability anisotropies, and first- and second-order hyperpolarizabilities of azoles. These properties are obtained with a finite field approach implemented in the DFT program ALLCHEM. The calculations were of all-electron type using a local exchange correlation functional. To investigate the dependence of polarizabilities and first- and second-order hyperpolarizabilities on the geometries, all structures were optimized with ALLCHEM and MSINDO. The influence of the substituted atoms on the properties is discussed. The vibrational contributions to the above properties of the considered compounds have also been computed using SCF theory and analytic property derivatives. Several methods (basis sets and approaches to determine the electron correlation contribution) have been employed to confirm the adequacy of the method, which was used. The electronic and vibrational properties are connected with var...

As part of a program to investigate the linear and nonlinear susceptibilities of acetonitrile in the condensed phase, we report on the accurate calculation of the molecular electric properties of acetonitrile, taking intoaccount geometry and basis set effects, static and dynamic electronic correlation, vibrational contributions, and frequency dispersion. All correlated single reference state methods as well as the multireference SCF with a Moller-Plesset second-order perturbation correction (MRMP2) yield similar values for the electronic contribution to the polarizability a and the second hyperpolarizability y. For the first hyperpolarizability, however, differences between the highly correlated methods CCSD(T) and MRMP2 remain. Vibrational contributions to the electric properties are calculated analytically and using two numerical finite difference methods at the Hartree-Fock level and at the correlated second-order Moller-Plesset level using finite field difference methods. Basis set convergence and convergence with the level of anharmonicity are examined. Computed values of the quantity μβ∥ (-2ω; ω, ω)/(3kT) + γ a v (-2ω; ω, ω, 0) agree with temperature-dependent experimental values at two different frequencies within 10%. Using the highest correlated methods, liquid-phase susceptibilities are computed in the dipolar Onsager reaction-field approximation. Excellent agreement with experiment for the relative permittivity and the refractive indices is found as well as acceptable agreement for the nonlinear susceptibility.

The interaction between AuOH and the lone-pair donors (HF, H2O) is shown to result in well-bound complexes whose structure resembles that of the corresponding H-bonded systems with the gold atom replacing hydrogen. The dissociation energies are estimated to be 10.7 and 27.4 kcal/mol for HF⋯Au–OH and H2O⋯Au–OH, respectively. However, the interaction between AuOH and the lone pair donors is found to involve significant charge transfer. Furthermore, the Au–O stretching frequency increases upon the complex formation. It is concluded that, in spite of certain similarity to the H-bonded species, the Au-bonded complexes should be considered as Lewis acid–base pairs.

An anti-inflammatory complex of Ag(I), namely [Ag(tpp)3(asp)](dmf) [tpp = triphenylphosphine, aspH = aspirin, dmf = N,N-dimethylformamide], was synthesized in an attempt to develop novel metallotherapeutic molecules. STD 1H NMR experiments were used to examine if this complex binds to LOX-1. The 1H NMR spectra in buffer Tris/D2O betrayed the existence of two complexes: the complex of aspirin and the complex of salicylic acid produced after deacetylation of aspirin. Nevertheless, the STD spectra showed that only the complex of salicylic acid is bound to the enzyme. Molecular docking and dynamics were used to complement our study. The complexes were stabilized inside a large LOX-1 cavity by establishing a network of hydrogen bonds and steric interactions. The complex formation with salicylic acid was more favorable. The in silico results provide a plausible explanation of the experimental results, which showed that only the complex with salicylic acid enters the binding cavity.

cited By 6; International audience; Starting from a hypothetical but fundamental charge/discharge sequence, the topic of nonlinear optical switching in atomic clusters built from silicon and alkali metals is opened up. The outcomes presented in this work, obtained with ab initio methods of exceptional predictive capabilities, offer strong evidences that sizable hyperpolarizability contrasts between neutral and charged alkali metal doped cluster forms might be simultaneously accomplished. The observed switching procedure involves redox polyatomic clusters formed by Si atoms. These centers function as electron acceptors at the ground state and as electron donors at the excited states facilitating low energy charge transfer transitions upon electronic excitation. © 2014 Wiley Periodicals, Inc. Accurate ab initio computations suggest that sizable hyperpolarizability contrasts between neutral and charged alkali metal doped silicon clusters might be simultaneously accomplished. The observed effect involves redox polyatomic centers formed by Si atoms. These centers function as electron acceptors at the ground state and as electron donors at the excited states, facilitating low energy charge-transfer transitions upon electronic excitation. © 2014 Wiley Periodicals, Inc.

Mutations in the human immunodeficiency virus (HIV) enable virus replication even when appropriate antiretroviral therapy is followed, thus leading to the emergence of drug resistance. In a previous work, we systematically examined seven single mutations that are associated with saquinavir (SQV) resistance in HIV-1 protease (Tzoupis, H.; Leonis, G.; Mavromoustakos, T.; Papadopoulos, M. G. J. Chem. Theory Comput. 2013, 9, 1754−1764). Herein, we extend our analysis, which includes seven double (G48VV82A, L10I-G48V, G48V-L90M, I84V-L90M, L10I-V82A, L10I-L63P, A71V-G73S) and four multiple (L10I-L63PA71V, L10I-G48V-V82A, G73S-I84V-L90M, L10I-L63PA71V-G73S-I84V-L90M) SQV−HIV-1 PR mutant complexes, in an attempt to generalize our findings and formulate the main elements of the SQV resistance mechanism in the protease. On the basis of molecular dynamics (MD), molecular mechanics Poisson−Boltzmann surface area (MM−PBSA), and ab initio computational approaches, we identified specific features that constitute the HIV-1 PR mechanism of resistance at the molecular level: the low flexibility of SQV in the binding cavity and the preservation of hydrogen bonding (HB) and van der Waals interactions between SQV and several active-site (Gly27/27′, Asp29/29′/30/30′, especially Asp25/25′) and flap (Ile50/50′, Gly48/48′) residues of the protease contribute significantly to efficient binding. The total enthalpy loss in all mutants is mostly due to the loss in enthalpy of the active-site region. Furthermore, it was observed that mutation accumulation may induce stabilization to SQV and to the flaps through enhanced HB interactions that lead to improved inhibition (e.g., accumulation of mutations in complexes containing L10I, G48V, L63P, I84V, or L90M single mutations). It was also concluded that permanent flap closure is obtained independently of mutations and SQV binding is mostly driven by van der Waals, nonpolar, and exchangeenergy contributions. Importantly, it was indicated that the optimal positioning of SQV and the structure of the binding cavity are tightly coupled, since small changes in geometry may affect the binding energy greatly. The results of our theoretical approaches are in agreement with experimental evidence and provide a reliable description of SQV resistance in HIV-1 PR.

For several years we have been working on the computation of the linear and non-linear optical (L&NLO) properties of organic molecules and on the design/selection of derivatives, which may have applications in the development of photonic devices. There is an intensive effort all over the world to discover the mechanisms and factors, which lead to large NLO properties, which are some of the properties required for materials to be useful in photonic applications. Here we review some of these factors, which lead to interesting or very large NLO properties.

Macroscopic first- and third-order susceptibilities of ice Ih, ice II, ice IX and ice VIII are calculated using static and frequency-dependent electronic and static vibrational molecular (hyper)polarizabilities at the MP2 level. The molecular properties are in good agreement with experiment and with high-level ab initio calculations. Intermolecular electrostatic and polarization effects due to induced dipoles are taken into account using a rigorous local-field theory. The electric field due to permanent dipoles is used to calculate effective in-crystal (hyper)polarizabilities. The polarizability depends only weakly on the permanent field, but the dipole moment and the hyperpolarizabilities are strongly affected. The calculated linear susceptibility is in good agreement with available experimental data for ice Ih, and the third-order susceptibility for a third harmonic generation experiment is in reasonable agreement with experimental values for liquid water. The molecular vibrational contributions have a small effect on the susceptibilities. The electric properties of a water tetramer are calculated and used to estimate the effect of non-dipolar interactions on the susceptibilities of ice Ih, which are found to be small.

The macroscopic first- to third-order susceptibilities of naphthalene, anthracene and meta-nitroaniline (mNA) are calculated using a rigorous local field approach. Molecular (hyper)polarizabilities used as input are determined by density functional theory calculations with specially designed basis sets and for mNA also by MP2 calculations with the 6-31++G** basis set. In the case of mNA, the permanent electric local field due to the surrounding dipoles in the crystal is taken into account for the first- and second-order susceptibility by a self-consistent approach. The molecular dipole moment and first hyperpolarizability of mNA are drastically changed by the permanent local field. In all cases the calculated first-order susceptibility compares very favorably with experimental data, if the molecular response is distributed over all heavy atoms in the molecules. Similarly, the calculated second-order susceptibility for mNA is in good agreement with available experimental data, if the same distribution scheme is used and the permanent local field is taken into account properly. This implies that accurate values for the molecular second-order hyperpolarizability c have to be available. The anisotropic Lorentz field factor approximation yields results that are only slightly worse than the best ones of the rigorous local field theory for the first-order susceptibilities, but fails for the second-order susceptibility of mNA, due to its incapability to describe the large eAect of the permanent local field on the first-order hyperpolarizability b. ” 2000 Elsevier Science B.V. All rights reserved.

We show how vibrational contributions to the static electric properties of polyatomic molecules may be computed with respect to arbitrary reference geometries. The derived geometry corrective term that compensates for the effect of using a non-optimum geometry, is a simple function of the energy gradient and first-order nuclear derivative of the electric property, summed over the number of normal vibrational modes of the molecule. We illustrate the possible orders of magnitude of the geometry correction for the major electric properties of the water molecule, computed at different levels of electronic structure theory: SCF, MP2, CCSD and CCSD(T).

This paper presents static polarizabilities, polarizability anisotropies, second hyperpolarizabilities, and an analysis of the vibrational effects for these polarizabilities of azabenzenes calculated in the framework of density functional theory. All molecular geometries were fully optimized. The calculations of the polarizabilities and second hyperpolarizabilities have been performed using a finite field approach implemented in the density functional program ALLCHEM. The calculations were of all-electron type using a local exchange-correlation functional. The calculated polarizabilities are in excellent quantitative agreement with available experimental data. The effect of the replacement of CH groups by N atoms is discussed.

We present a semi-numerical method based on Numerov–Cooley (NC) integration for calculating vibrational corrections to static electric properties of diatomic molecules. The approach exploits the Born–Oppenheimer energy and property functions, utilizing such information in the NC integration of the field-dependent vibrational equation, in a way which exposes separate contributions to the total electric property. The scheme is illustrated by computation of electronic and vibrational contributions to the dipole polarizability and first hyperpolarizability of the KLi dimer. A comparison with results obtained from finite-order perturbation theory reveals various sources of anharmonicity.

The electronic structure of the fully lithiated benzene molecule has been calculated at different levels of approximation with particular attention paid to its second hyperpolarizability. It has been estimated that lithiation of the benzene molecule may lead to the enormous increase of the second hyperpolarizability. For hexalithiobenzene the second hyperpolarizability term responsible for the third harmonic generation has been estimated to be of the order of 107e4ao4Eh−3. The reasons for the very large increase of the dipole polarizability, and in particular, of the second hyperpolarizability upon lithiation have been analysed in terms of the electronic structure, orbital energy levels, and the excitation spectrum of the hexalithiobenzene molecule. The main factor responsible for the particularly large values of the studied properties is the electronic valence shell structure of the lithium atom. Although the hexalithiobenzene molecule is used as a model for the study of the lithiation effect, several stable organometallic systems involving alkali metals are known. The present study suggests that among these systems one may find materials of extremly high nonlinear optical efficiency.

Macroscopic first-, second-, and third-order susceptibilities of the urea crystal are calculated using static and frequency-dependent ab initio molecular (hyper)polarizabilities at the self-consistent field (SCF) and second-order-Mo/ller–Plesset (MP2) levels. Environmental effects are taken into account using a rigorous local-field theory and are compared with the anisotropic Lorentz field factor approximation. The electric field arising from the permanent dipoles of the surrounding molecules is explicitly taken into account using a self-consistent approach. The dipole moment and the first hyperpolarizability are particularly strongly dependent on this field, but the crystal structure leads to a fortuitous cancellation of the field effect on the second-order susceptibility. The experimental linear susceptibility is accurately reproduced, while differences remain for the quadratic susceptibility. Dispersion curves for the first-order susceptibility, and results for quadratic electrooptic effect (QEO), elec...

Electronic, vibrational and rotational contributions to the dipole moment μ, polarizability α, and first and second hyperpolarizabilities, β and γ, are presented for the boron hydride molecule; static and dynamic rovibrational properties are reported for the first time. The electronic contributions are computed ab initio by finite differencing the electronic energy computed at the Hartree–Fock level of theory, and using various sophisticated correlated methods. Specifically these are Mo/ller–Plesset perturbation theory at second order, and fourth order (including single, double, triple and quadruple substitutions), and the Brueckner variant of the coupled-cluster method including triple excitations; density functional theory with the B3LYP functional is used for comparison. Vibrational (and rotational) contributions to the properties are calculated at the Hartree–Fock level of theory; for the vibrational properties, electron correlation is partially included using second order Mo/ller–Plesset theory. Basi...

The beryllium atom embedded in He clusters of octahedral and cubic symmetry is studied as a model of a highly polarizable system surrounded by a relatively inert and weakly polarizable medium. The coupled cluster calculations with single and double excitations corrected for triple excitations predict that the dipole polarizability and hyperpolarizability of the `in-cluster' Be atom are significantly reduced in comparison with the free-atom values. In the vicinity of the van der Waals minima this reduction amounts to about ten percent of the Be atom hyperpolarizability. This orbital compression effect shows that in the modeling of highly nonlinear optical materials one must explicitly consider the presence of the medium.

The emergence of HIV-1 drug-resistant mutations is the major problem against AIDS treatment. We employed molecular dynamics (MD) calculations and free energy (MM-PBSA and thermodynamic integration) analyses on wild-type (WT) and mutated HIV-1 protease (HIV-1 PR) complexes with darunavir, amprenavir, indinavir, and saquinavir to clarify the mechanism of resistance due to the I50V flap mutation. Conformational analysis showed that the protease flaps are increasingly flexible in the I50V complexes. In the WT, stabilization of the HIV-1 PR structure is achieved via interflap and water-mediated hydrogen-bonding interactions between the flaps. Furthermore, hydrogen bonds between drugs and binding cavity residues (Asp29/29'/30/30') are crucial for effective inhibition. All these interactions were significantly diminished (or absent) in the mutated forms, thus denoting their importance toward binding. Thermodynamic integration calculations reproduced the experimental data to within ≈1 kcal mol⁻¹ and showed that the I50V mutation results in weaker binding free energies for all analyzed complexes with respect to the WT. It was observed that the loss in binding energy upon mutation was mostly enthalpically driven in all complexes, with the greatest effect coming from the reduction of van der Waals interactions. Our results motivated us to test two novel compounds that have been synthesized to maximize interactions with HIV-1 PR. MM-PBSA and TI calculations showed that compound 3c (Ghosh et al. Bioorg. Med. Chem. Lett. 2012, 22, 2308) is a promising protease inhibitor, which presents very effective binding to the WT PR (ΔG(MM-PBSA) = -17.2 kcal mol⁻¹, ΔG(exp) = -16.1 kcal mol⁻¹). Upon I50V mutation, the complex binding free energy was weakened by a ΔΔG(TI) of 1.8 kcal mol⁻¹, comparable to the marketed inhibitors. This predicts that I50V may confer low resistance to 3c. This computational comparative study contributes toward elucidation of the I50V drug-resistance mechanism in HIV-1 PR.

A set of exchange-correlation functionals, including BLYP, PBE0, B3LYP, BHandHLYP, CAM-B3LYP, LC-BLYP, and HSE, has been used to determine static and dynamic nonresonant (nuclear relaxation) vibrational (hyper)polarizabilities for a series of all-trans polymethineimine (PMI) oligomers containing up to eight monomer units. These functionals are assessed against reference values obtained using the Moller–Plesset second-order perturbation theory (MP2) and CCSD methods. For the smallest oligomer, CCSD(T) calculations confirm the choice of MP2 and CCSD as appropriate for assessing the density functionals. By and large, CAM-B3LYP is the most successful, because it is best for the nuclear relaxation contribution to the static linear polarizability, intensity-dependent refractive index second hyperpolarizability, static second hyperpolarizability, and is close to the best for the electro-optical Pockels effect first hyperpolarizability. However, none of the functionals perform satisfactorily for all the vibrational (hyper)polarizabilities studied. In fact, in the case of electric field-induced second harmonic generation all of them, as well as the Hartree–Fock approximation, yield the wrong sign. We have also found that the Pople 6–31+G(d) basis set is unreliable for computing nuclear relaxation (hyper)polarizabilities of PMI oligomers due to the spurious prediction of a nonplanar equilibrium geometry. © 2013 Wiley Periodicals, Inc.

The vibrational (hyper)polarizabilities of some selected Xe derivatives are studied in the context of Bishop–Kirtman perturbation theory (BKPT) and numerical finite field methodology. It was found that for this set of rare gas compounds, the static vibrational properties are quite large, in comparison to the corresponding electronic ones, especially those of the second hyperpolarizability. This also holds for the dc-Pockels β(−ω;ω,0), Kerr γ(−ω;ω,0,0) and electric field second harmonic generation γ (−2ω;ω,ω,0) effects, although the computed nuclear relaxation (nr) vibrational contributions are smaller in magnitude than the static ones. HXeOXeH was used to study the effects of electron correlation, basis set, and geometry. Geometry effects were found to lead to noticeable changes of the vibrational and electronic second hyperpolarizability. A limited study of the effect of Xe insertion to the nr vibrational properties is also reported. Assessment of the results revealed that Xe insertion has a remarkable effect on the nr (hyper)polarizabilities. In terms of the BKPT, this is associated with a remarkable increase of the electrical and mechanical anharmonicity terms. The latter is consistent with the anharmonic character of several vibrational modes reported for rare gas compounds. © 2013 Wiley Periodicals, Inc.

The linear and nonlinear optical (L&NLO) properties, the energy difference between the highest occupied molecular orbital and the lowest unoccupied molecular orbital (HOMO–LUMO gap), the first excitation energy (Eexc), and four indices for the evaluation of the diradical character (DC) of a series of Ni dithiolene derivatives have been computed by employing density functional theory (DFT). The selected DFT functionals provide reliable results for several properties [e.g., excitation energies and (hyper)polarizabilities]. An Atoms in Molecules analysis has been performed and several related properties have been reported (e.g., the average delocalization index, charge density, and its Laplacian). The selected derivatives with regular structural changes allow us to trace correlations between the (hyper)polarizabilities and some of the computed properties (e.g., Eexc and the DC indices). A small change in the structure may lead to a very large change of the diradical character and the L&NLO properties. Several of the studied derivatives have an exceptionally large second hyperpolarizability. Thus, the considered set of Ni dithiolene derivatives is likely to have applications in the development of photonic devices.

The electronic contributions to the dipole moment, the polarizabilities, first and second hyperpolarizabilities for LiH are computed using basis sets for H involving two variations of a set comprising 10s 7p 5d GTOs, while for Li several large basis sets (e.g. (13s 8p 6d 2f)/[8s 5p 3d 1f] and 13s 7p 3d 1f) have been employed. Electron correlation has been taken into account using MP4[SDTQ] theory. The effect of the nuclear motion on the dipole moment and some components of the polarizability and hyperpolarizabilities is computed at the SCF level employing a finite perturbation theory approach. The vibrational contribution to the above properties is calculated for the ground and the first four excited vibrational states. We have found that vibrational contributions are not negligible and one (βzzz) has a significant magnitude.

The electronic contribution to the components of the static polarizability and second hyperpolarizability of Li2 is studied using SCF, MP2 and MP4[SDTQ] theories with several large basis sets. The computed polarizability is within the experimental error limits. The static vibrational contributions to these properties are also determined. The nuclear motion has a considerable effect on the second hyperpolarizability but not on the polarizability.

Various procedures for designing basis sets to be used in the computation of high‐quality wave functions have been considered. The most satisfactory results for the polarizability and hyperpolarizabilities of He, H2, Be, Ne, F−, and HF were obtained using the core basis sets of van Duijneveldt, augmented by 7f1(l+1)5f2(l+2), where f1 and f2 are polarization Gaussian‐type functions which are energy optimized and l defines the symmetry of the highest occupied subshell of the atom. Subsequently, simple rules, like replacing the 2s and 2f functions having the largest exponents with an equal number of orbitals of the same symmetry, the exponents of which form a geometric or even‐tempered sequence with the two most diffuse exponents, have been used. Correlation effects are taken into account using fourth‐order Mo/ller–Plesset perturbation theory.

Human immunodeficiency virus type 1 protease (HIV-1 PR) and renin are primary targets toward AIDS and hypertension therapies, respectively. Molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) free-energy calculations and inhibition assays for canagliflozin, an antidiabetic agent verified its effective binding to both proteins (ΔG(pred) = -9.1 kcal mol(-1) for canagliflozin-renin; K(i,exp)= 628 nM for canagliflozin-HIV-1 PR). Moreover, drugs aliskiren (a renin inhibitor) and darunavir (an HIV-1 PR inhibitor) showed high affinity for HIV-1 PR (K(i,exp)= 76.5 nM) and renin (K(i,pred)= 261 nM), respectively. Importantly, a high correlation was observed between experimental and predicted binding energies (r(2) = 0.92). This study suggests that canagliflozin, aliskiren, and darunavir may induce profound effects toward dual HIV-1 PR and renin inhibition. Since patients on highly active antiretroviral therapy (HAART) have a high risk of developing hypertension and diabetes, aliskiren-based or canagliflozin-based drug design against HIV-1 PR may eliminate these side-effects and also facilitate AIDS therapy.

Drug-membrane interactions of the candesartan cilexetil (TCV-116) have been studied on molecular basis by applying various complementary biophysical techniques namely differential scanning calorimetry (DSC), Raman spectroscopy, small and wide angle X-ray scattering (SAXS and WAXS), solution ¹H and ¹³C nuclear magnetic resonance (NMR) and solid state ¹³C and ³¹P (NMR) spectroscopies. In addition, ³¹P cross polarization (CP) NMR broadline fitting methodology in combination with ab initio computations has been applied. Finally molecular dynamics (MD) was applied to find the low energy conformation and position of candesartan cilexetil in the bilayers. Thus, the experimental results complemented with in silico MD results provided information on the localization, orientation, and dynamic properties of TCV-116 in the lipidic environment. The effects of this prodrug have been compared with other AT₁ receptor antagonists hitherto studied. The prodrug TCV-116 as other sartans has been found to be accommodated in the polar/apolar interface of the bilayer. In particular, it anchors in the mesophase region of the lipid bilayers with the tetrazole group oriented toward the polar headgroup spanning from water interface toward the mesophase and upper segment of the hydrophobic region. In spite of their localization identity, their thermal and dynamic effects are distinct pointing out that each sartan has its own fingerprint of action in the membrane bilayer, which is determined by the parameters derived from the above mentioned biophysical techniques.

We have performed: (i) conformational analysis of two novel cytotoxic C2-substituted pyrrolo[2,3- f ]quinolines 5e and 5g in deuterated dimethylsulfoxide (DMSO- d 6 ) utilizing NOE results from NMR spectroscopy; (ii) molecular dynamics (MD) calculations in water, DMSO and dimyristoyl phosphatidylcholine bilayers and (iii) molecular docking and MD calculations on DNA nucleotide sequences. The obtained results for the two similar in structure molecules showed differences in: (i) their conformational properties in silico and in media that reasonably simulate the biological environment; (ii) the way they are incorporated into the lipid bilayers and therefore their diffusion ability and (iii) molecular docking capacity as it is depicted from their different binding scores.

Human immunodeficiency virus type 1 protease (HIV-1 PR) is one of the main targets toward AIDS therapy. We have selected the potent drug darunavir and a weak inhibitor (fullerene analog) as HIV-1 PR substrates to compare protease's conformational features upon binding. Molecular dynamics (MD), molecular mechanics Poisson-Boltzmann surface area (MM-PBSA), and quantum-mechanical (QM) calculations indicated the importance of the stability of HIV-1 PR flaps toward effective binding: a weak inhibitor may induce flexibility to the flaps, which convert between closed and semiopen states. A water molecule in the darunavir-HIV-1 PR complex bridged the two flap tips of the protease through hydrogen bonding (HB) interactions in a stable structure, a feature that was not observed for the fullerene-HIV-1 PR complex. Additionally, despite that van der Waals interactions and nonpolar contribution to solvation favored permanent fullerene entrapment into the cavity, these interactions alone were not sufficient for effective binding; enhanced electrostatic interactions as observed in the darunavir-complex were the crucial component of the binding energy. An alternative pathway to the usual way of a ligand to access the cavity was also observed for both compounds. Each ligand entered the binding cavity through an opening between the one flap of the protease and a neighboring loop. This suggested that access to the cavity is not necessarily regulated by flap opening. Darunavir exerts its biological action inside the cell, after crossing the membrane barrier. Thus, we also initiated a study on the interactions between darunavir and the DMPC bilayer to reveal that the drug was accommodated inside the bilayer in conformations that resembled its structure into HIV-1 PR, being stabilized via HBs with the lipids and water molecules.

A general reduced dimensionality finite-field nuclear relaxation method for calculating vibrational nonlinear optical properties of molecules with large contributions due to anharmonic motions has been very recently devolped. Both nuclear relaxation and curvature contributions are included. In an initial application to the umbrella (inversion) motion of NH3 it is found that the initial convergence problems associated with a conventional single well treatment are overcome and that the particular definition of the inversion coordinate is not important.

Recent studies of the linear and nonlinear electric properties of various fullerene-based subsystems are reviewed. The electric properties of derivatives of C60 fullerene with carbazole, benzothiazole, benzothiazole-triphenyloamine and free-base porphyrin substituents at different levels of theory are summarized. In addition, the electronic and vibrational electric properties of endohedral Sc2@C72 system are reported.

Despite undisputed success of the density functional theory (DFT) in various branches of chemistry and physics, an application of the DFT for reliable predictions of nonlinear optical properties of molecules has been questioned a decade ago. As it was shown by Champagne, et al. [1, 2, 3] most conventional DFT schemes were unable to qualitatively predict the response of conjugated oligomers to a static electric field. Long-range corrected (LRC) functionals, like LC-BLYP or CAM-B3LYP, have been proposed to alleviate this deficiency. The reliability of LRC functionals for evaluating molecular (hyper)polarizabilities is studied for various groups of organic systems, with a special focus on vibrational corrections to the electric properties.

The vibrational contributions to the linear and nonlinear optical properties (L&NLO) of some selected systems are reported. The Bishop-Kirtman perturbation approach as well the Numerov-Cooley technique were employed for the computation of the vibrartional properies. Electron correlation and relativistic effects have been considered. The results show that the vibrational contributions are essential for the reasonably accurate description of the L&NLO properties and in particular of the first and second order hyperpolarizabilities.

The electronic ground state, stability, and linear and nonlinear optical properties of HXeOXeF and FXeOXeF have been studied theoretically by employing complete active space valence bond (CASVB), multistate complete active space perturbation theory (MS-CASPT2), and coupled cluster methods. It is shown that the oxygen inserted between the two Xe atoms significantly modifies the ground-state electronic configuration of the formed derivative by increasing the closed-shell contribution (σ(2)) and removing the diradicaloid character observed in HXe(2)F. The electronic charge distribution has been analyzed by employing the atoms-in-molecules (AIM) method. The dissociation channels of HXeOXeF and FXeOXeF have been studied in detail. It was found that these compounds are metastable, protected by substantial energy barriers and, thus, they can be prepared under appropriate conditions. Both two- and three-body dissociation reactions have been considered. The effects of inserting O in HXe(2)F and substituting H (HXeOXeF) by F, leading to FXeOXeF, on the energy barriers are discussed. The significant effects of the inserted oxygen on the polarizability and even more on the first hyperpolarizability have been computed and rationalized.

We report the partitioning of the interaction-induced static electronic dipole (hyper)polarizabilities for linear hydrogen cyanide complexes into contributions arising from various interaction energy terms. We analyzed the nonadditivities of the studied properties and used these data to predict the electric properties of an infinite chain. The interaction-induced static electric dipole properties and their nonadditivities were analyzed using an approach based on numerical differentiation of the interaction energy components estimated in an external electric field. These were obtained using the hybrid variational-perturbational interaction energy decomposition scheme, augmented with coupled-cluster calculations, with singles, doubles, and noniterative triples. Our results indicate that the interaction-induced dipole moments and polarizabilities are primarily electrostatic in nature; however, the composition of the interaction hyperpolarizabilities is much more complex. The overlap effects substantially quench the contributions due to electrostatic interactions, and therefore, the major components are due to the induction and exchange-induction terms, as well as the intramolecular electron-correlation corrections. A particularly intriguing observation is that the interaction first hyperpolarizability in the studied systems not only is much larger than the corresponding sum of monomer properties, but also has the opposite sign. We show that this effect can be viewed as a direct consequence of hydrogen-bonding interactions that lead to a decrease of the hyperpolarizability of the proton acceptor and an increase of the hyperpolarizability of the proton donor. In the case of the first hyperpolarizability, we also observed the largest nonadditivity of interaction properties (nearly 17%) which further enhances the effects of pairwise interactions.

A general reduced dimensionality finite field nuclear relaxation method for calculating vibrational nonlinear optical properties of molecules with large contributions due to anharmonic motions is introduced. In an initial application to the umbrella (inversion) motion of NH(3) it is found that difficulties associated with a conventional single well treatment are overcome and that the particular definition of the inversion coordinate is not important. Future applications are described.

This article reviews some recent works, which deal with state-of-the-art results linear and nonlinear (L&NLO) properties of molecules (organic and inorganic). The electronic correlation, vibrational and relativistic contributions have been computed. Correlation has been taken into account by employing a series of methods e.g. MP2, CCSD, CCSD(T), CASPT2. The vibrational contributions have been computed by using the Bishop and Kirtman perturbation theory as well as the Numerov-Cooley integration. The relativistic correction has been computed by using the Douglas-Kroll method. It is noted that vibrational contribution has been calculated by taking into account both correlation and relativistic corrections. The properties are mainly static, but to a smaller extent, we have also considered frequency dependent properties. The main emphasis of the reviewed works was to use all the computational tools currently available in order to calculate property values as accurate as it is currently possible. The accuracy of the employed approximations is evaluated and discussed. Several interesting features and trends have been observed, for example the relativistic effects significantly reduce the magnitude of the vibrational corrections (coinage metal hydrides). An extensive study of fullerenes and endohedral fullerenes has been performed and reviewed. Of particular interest is the effect of the endohedral atom (e.g. Li) on the L&NLO properties of the system. The reviewed works have employed a large variety of systems (e.g. heavy metal -Group IIb- sulfides, coinage metal hydrides, ketones, thiones etc.).

The potential energy surface (PES) of Ti@C(28) has been revisited, and the stationary points have been carefully characterized. In particular, the C(2v) symmetry structure considered previously turns out to be a transition state lying 2.3 kcal/mol above the ground state of C(3v) symmetry at the MP2/6-31G(d) level. A large binding energy of 181.3 kcal/mol is found at the ROMP2/6-31G(d) level. Topological analysis of the generalized Ti@C(28) density reveals four bond paths between Ti and carbon atoms of the host. The character of all four contacts corresponds to a partially covalent closed shell interaction. UV-vis, IR, and Raman spectra are calculated and compared with C(28)H(4). The dipole moment and the static electronic and double harmonic vibrational (hyper)polarizabilities have been obtained. Distortion of the fullerene cage due to encapsulation leads to nonzero diagonal components of the electronic first hyperpolarizability β, and to an increase in the diagonal components of the electronic polarizability α and second hyperpolarizability γ. However, introduction of the Ti atom causes a comparable or larger reduction in most cases due to localized bonding interactions. At the double harmonic level, the average vibrational β is much larger than its electronic counterpart, but the opposite is true for α and for the contribution to γ that has been calculated. There is also a very large anharmonic (nuclear relaxation) contribution to β which results from a shallow PES with four minima separated by very low barriers. Thus, the vibrational γ (and α) may, likewise, become much larger when anharmonicity is taken into account.

The new molecule 4-[(2S)-2-(1H-imidazol-1-ylmethyl)-5-oxotetrahydro-1H-pyrrol-1-yl]methylbenzenecarboxylic acid (MMK16) was found to have promising anti-inflammatory activity. This biological behavior of MMK16 triggered our interest to study its binding affinity using NMR spectroscopy in LOX and its docking and molecular dynamics (MD) properties in LOX and COX enzymes. The present NMR and docking binding studies not only rationalize the obtained biological results since in all three receptors MMK16 shows high affinity and scoring but also make it a potential dual LOX-5/COX-2 inhibitor. Thus, this class of molecules must be further investigated for discovering compounds possessing better biological activity and more lasting biological effect.