Manthos G. Papadopoulos

Linear and Nonlinear Optical Properties of (60)Fullerene Derivatives

Using a wide variety of quantum-chemical methods we have analyzed in detail the linear and non-linear optical properties of [60]fullerene-chromophore dyads of different electron-donor character. The dyads are composed of [60]fullerene covalently linked with 2,1,3-benzothiadiazole and carbazole derivatives. Linear scaling calculations of molecular (hyper)polarizabilities were performed using wave function theory as well as density functional theory (DFT). Within the former approach, we used both semiempirical (PM3) and ab initio (Hartree-Fock and second-order Møller-Plesset perturbation theory) methods. Within the latter approach only the recently proposed long-range (LRC) schemes successfully avoid a large overshoot in the value obtained for the first hyperpolarizability (β). Calculations on model fullerene derivatives establish a connection between this overshoot and the electron-donating capability of the substituent. Substitution of 2,1,3-benzothiadiazole by the triphenylamine group significantly increases the electronic first and second hyperpolarizabilities as well as the two-photon absorption cross section. For [60]fullerene-chromophore dyads we have, additionally, observed that the double harmonic vibrational contribution to the static beta is much larger than its electronic counterpart. The same is true for the dc-Pockels β as compared to the static electronic value, although the vibrational term is reduced in magnitude; for the intensity-dependent refractive index the vibrational and electronic terms are comparable. A nuclear relaxation treatment of vibrational anharmonicity for a model fulleropyrrolidine molecule yields a first-order contribution that is substantially more important than the double harmonic term for the static β.

Computational design of novel fullerene analogues as potential HIV-1 PR inhibitors: Analysis of the binding interactions between fullerene inhibitors and HIV-1 PR residues using 3D QSAR, molecular docking and molecular dynamics simulations.

A series of experimentally reported as well as computationally designed monoadducts and bisadducts of [60]fullerene analogues have been used in order to analyze the binding interactions between fullerene based inhibitors and HIV-1 PR employing docking studies. MD simulations of ligand-free and the inhibitor bound HIV-1 PR systems complemented the above studies and provided proper input structure of HIV-1 PR in docking simulations. The obtained results revealed a different orientation of the beta-hairpin flaps at these two systems. In inhibitor bound system, the flaps of the enzyme are pulled in toward the bottom of the active site (the closed form) while, in ligand-free system flaps shifted away from the dual Asp25 catalytic site and this system adopts a semi-open form. The structural analysis of these systems at catalytic and flexible flap regions of the HIV-1 PR through the simulation, assisted in understanding the structural preferences of these regions, as well as, the adopted orientations of fullerene derivatives within the active site of the enzyme. Five different combinations of steroelectronic fields of 3D QSAR/CoMSIA models were obtained from the set of biologically evaluated and computationally designed fullerene derivatives (training set=43, test set=6) in order to predict novel compounds with improved inhibition effect. The best 3D QSAR/CoMSIA model yielded a cross validated r(2) value of 0.739 and a non-cross validated r(2) value of 0.993. The derived model indicated the importance of steric (42.6%), electrostatic (12.7%), H-bond donor (16.7%) and H-bond acceptor (28.0%) contributions. The derived contour plots together with de novo drug design were then used as pilot models for proposing the novel analogues with enhanced binding affinities. Such structures may trigger the interest of medicinal chemists for novel HIV-1 PR inhibitors possessing higher bioactivity.

Calculation of macroscopic first-, second-, and third-order optical susceptibilities for the urea crystal

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...

Linear-Scaling Techniques in Computational Chemistry and Physics

Including chapters on: Linear scaling second order Moller Plesset perturbation theory.- Divide-and-conquer approaches to quantum chemistry: Theory and implementation.- Mathematical formulation of the fragment molecular orbital method.- Linear scaling for metallic systems by the Korringa-Kohn-Rostoker multiple-scattering method.- Density matrix methods in linear scaling electronic structure theory.- Methods for Hartree-Fock and density functional theory electronic structure calculations with linearly scaling processor time and memory usage.- Some thoughts on the scope of the linear scaling self-consistent field electrnic structure methods.- The linear scaling semiempirical localSCF method and the finite LMO approximation.- Molecular Tailoring: an Art of the Possible for Ab Initio Treatment of Large Molecules and Molecular Clusters.- Local approximations for an efficient treatment of electron correlation and electron excitations in molecules.

3D QSAR CoMFA/CoMSIA, molecular docking and molecular dynamics studies of fullerene-based HIV-1 PR inhibitors

For the first time, a set of experimentally reported [60] fullerene derivatives were subjected to the 3D-QSAR/CoMFA and CoMSIA studies. The aim of this study is to propose a series of novel [60] fullerene-based inhibitors with optimal binding affinity for the HIV-1 PR enzyme. The position of the template molecule at the cavity of HIV-1 PR was optimized and 3D QSAR models were developed. Relative contributions of steric/electrostatic fields of the 3D-QSAR/CoMFA and CoMSIA models have shown that steric effects govern the bioactivity of the compounds, but electrostatic interactions play also an important role.The de novo drug design Leapfrog simulations provided a series of novel compounds with predicted improved inhibition effect.

Calculation of macroscopic linear and nonlinear optical susceptibilities for the naphthalene, anthracene and meta-nitroaniline crystals

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.

Distributed first and second order hyperpolarizabilities: An improved calculation of nonlinear optical susceptibilities of molecular crystals

The method of calculating distributed polarizabilities is extended to the first and second dipole hyperpolarizabilities, in order to describe more accurately the molecular response to strong and inhomogeneous external time-dependent electric fields. The dipolar response is expressed in terms of both potential related charge-density response functions and electric field related dipole-density response functions. The macroscopic linear, quadratic, and cubic optical dipole susceptibilities of molecular crystals are expressed in terms of the distributed (hyper) polarizabilities. This formulation differs from previous theories using distributed dipoles in that it allows for a rigorous treatment of both local induced dipoles and charge flow between different regions of the molecule. As an example, the distributed polarizabilities and first hyperpolarizabilities of urea at the self-consistent-field level are used to calculate the linear and quadratic susceptibilities of the urea crystal. The linear susceptibilit...

Strategies in the rational drug design.

Rational design is applied in the discovery of novel lead drugs. Its rapid development is mainly attributed to the tremendous advancements in the computer science, statistics, molecular biology, biophysics, biochemistry, medicinal chemistry, pharmacokinetics and pharmacodynamics experienced in the last few decades. The promising feature that characterizes the application of rational drug design is that it uses for developing potential leads in drug discovery all known theoretical and experimental knowledge of the system under study. The utilization of the knowledge of the molecular basis of the system ultimately aims to reduce human power cost, time saving and laboratory expenses in the drug discovery. In this review paper various strategies applied for systems which include: (i) absence of knowledge of the receptor active site; (ii) the knowledge of a homology model of a receptor, (iii) the knowledge of the experimentally determined (i.e. X-ray crystallography, NMR spectroscopy) coordinates of the active site of the protein in absence and (iv) the presence of the ligand will be analyzed.

In Silico Drug Screening Approach for the Design of Magic Bullets: A Successful Example with Anti-HIV Fullerene Derivatized Amino Acids

A database has been derived from recently reported [60]fullerene derivatives, and their binding scores with HIV-1 PR have been computed using docking techniques. Computational methods have been used to predict which derivatives may have high binding affinities, and for these compounds biological tests have been performed with purified PR. Experimental results confirm the high binding scores of fullerene derivatives predicted from the docking calculations. Our measurements showed that the fullerene derivative (Fmoc-Baa) has about three times better inhibitory binding (K(i) = 36 nM) than the most active fullerene-based inhibitor (K(i) = 103 nM) currently available.

Electronic and vibrational contributions to first hyperpolarizability of donor-acceptor-substituted azobenzene.

In this study we report on the electronic and vibrational (hyper)polarizabilities of donor-acceptor-substituted azobenzene. It is observed that both electronic and vibrational contributions to the electric dipole first hyperpolarizability of investigated photoactive molecule substantially depend on the conformation. The contributions to the nuclear relaxation first hyperpolarizability are found to be quite important in the case of two considered isomers (cis and trans). Although the double-harmonic term is found to be the largest in terms of magnitude, it is shown that the total value of the nuclear relaxation contribution to vibrational first hyperpolarizability is a result of subtle interplay of higher-order contributions. As a part of the study, we also assess the performance of long-range-corrected density functional theory in determining vibrational contributions to electric dipole (hyper)polarizabilities. In most cases, the applied long-range-corrected exchange-correlation potentials amend the drawbacks of their conventional counterparts.