MP2 and CCSD(T) complete basis set (CBS) limit interaction energies and geometries for more than 100 DNA base pairs, amino acid pairs and model complexes are for the first time presented together. Extrapolation to the CBS limit is done by using two-point extrapolation methods and different basis sets (aug-cc-pVDZ - aug-cc-pVTZ, aug-cc-pVTZ - aug-cc-pVQZ, cc-pVTZ - cc-pVQZ) are utilized. The CCSD(T) correction term, determined as a difference between CCSD(T) and MP2 interaction energies, is evaluated with smaller basis sets (6-31G** and cc-pVDZ). Two sets of complex geometries were used, optimized or experimental ones. The JSCH-2005 benchmark set, which is now available to the chemical community, can be used for testing lower-level computational methods. For the first screening the smaller training set (S22) containing 22 model complexes can be recommended. In this case larger basis sets were used for extrapolation to the CBS limit and also CCSD(T) and counterpoise-corrected MP2 optimized geometries were sometimes adopted.

Standard density functional theory (DFT) is augmented with a damped empirical dispersion term. The damping function is optimized on a small, well balanced set of 22 van der Waals (vdW) complexes and verified on a validation set of 58 vdW complexes. Both sets contain biologically relevant molecules such as nucleic acid bases. Results are in remarkable agreement with reference high-level wave function data based on the CCSD(T) method. The geometries obtained by full gradient optimization are in very good agreement with the best available theoretical reference. In terms of the standard deviation and average errors, results including the empirical dispersion term are clearly superior to all pure density functionals investigated-B-LYP, B3-LYP, PBE, TPSS, TPSSh, and BH-LYP-and even surpass the MP2/cc-pVTZ method. The combination of empirical dispersion with the TPSS functional performs remarkably well. The most critical part of the empirical dispersion approach is the damping function. The damping parameters should be optimized for each density functional/basis set combination separately. To keep the method simple, we optimized mainly a single factor, s(R), scaling globally the vdW radii. For good results, a basis set of at least triple-zeta quality is required and diffuse functions are recommended, since the basis set superposition error seriously deteriorates the results. On average, the dispersion contribution to the interaction energy missing in the DFT functionals examined here is about 15 and 100% for the hydrogen-bonded and stacked complexes considered, respectively.

Scaled MP3 interaction energies calculated as a sum of MP2/CBS (complete basis set limit) interaction energies and scaled third-order energy contributions obtained in small or medium size basis sets agree very closely with the estimated CCSD(T)/CBS interaction energies for the 22 H-bonded, dispersion-controlled and mixed non-covalent complexes from the S22 data set. Performance of this so-called MP2.5 (third-order scaling factor of 0.5) method has also been tested for 33 nucleic acid base pairs and two stacked conformers of porphine dimer. In all the test cases, performance of the MP2.5 method was shown to be superior to the scaled spin-component MP2 based methods, e.g. SCS-MP2, SCSN-MP2 and SCS(MI)-MP2. In particular, a very balanced treatment of hydrogen-bonded compared to stacked complexes is achieved with MP2.5. The main advantage of the approach is that it employs only a single empirical parameter and is thus biased by two rigorously defined, asymptotically correct ab-initio methods, MP2 and MP3. The method is proposed as an accurate but computationally feasible alternative to CCSD(T) for the computation of the properties of various kinds of non-covalently bound systems.

Mitochondrial complex II (CII) has been recently identified as a novel target for anti-cancer drugs. Mitochondrially targeted vitamin E succinate (MitoVES) is modified so that it is preferentially localized to mitochondria, greatly enhancing its pro-apoptotic and anti-cancer activity. Using genetically manipulated cells, MitoVES caused apoptosis and generation of reactive oxygen species (ROS) in CII-proficient malignant cells but not their CII-dysfunctional counterparts. MitoVES inhib-ited the succinate dehydrogenase (SDH) activity of CII with IC 50 of 80 M, whereas the electron transfer from CII to CIII was inhibited with IC 50 of 1.5 M. The agent had no effect either on the enzymatic activity of CI or on electron transfer from CI to CIII. Over 24 h, MitoVES caused stabilization of the oxygen-dependent destruction domain of HIF1␣ fused to GFP, indicating promotion of the state of pseudohypoxia. Molecular modeling predicted the succinyl group anchored into the proximal CII ubiquinone (UbQ)-binding site and successively reduced interaction energies for serially shorter phytyl chain homologs of MitoVES correlated with their lower effects on apoptosis induction, ROS generation, and SDH activity. Mutation of the UbQ-binding Ser 68 within the proximal site of the CII SDHC subunit (S68A or S68L) suppressed both ROS generation and apoptosis induction by MitoVES. In vivo studies indicated that MitoVES also acts by causing pseudohypoxia in the context of tumor suppression. We propose that mitochondrial targeting of VES with an 11-carbon chain localizes the agent into an ideal position across the interface of the mitochondrial inner membrane and matrix, optimizing its biological effects as an anti-cancer drug.Mitochondria are emerging as targets for a variety of anti-cancer drugs (1-5) that belong to a group of compounds termed "mitocans" (6, 7). Of these agents, we and others have been studying the group of vitamin E (VE) 2 analogs, epitomized by the "redox-silent" ␣-tocopheryl succinate (␣-TOS) and ␣-tocopheryl acetyl ether (8). Both of these agents proved to be selective inducers of apoptosis in cancer cells and efficient suppressors of tumors in experimental models (9 -16).VE analogs with anti-cancer activity have been classified as mitocans (i.e. small anti-cancer agents that act by selectively destabilizing mitochondria in cancer cells) (6 -8). Of the several groups of mitocans, the anti-cancer VE analogs belong to both the class of BH3 mimetics, which includes compounds interfering with the interactions of the Bcl-2 family proteins (17), as well as to the class of agents that interfere with the mitochondrial electron redox chain. The latter activity is probably the main reason for the strong apoptogenic efficacy of agents like ␣-TOS (18). More specifically, ␣-TOS interferes * This work was supported by grants from the Australian Research Council,

Single crystal molecular structure and solution photophysical properties are reported for 1,3-diphenylisobenzofuran (1), of interest as a model compound in studies of singlet fission. For the ground state of 1 and of its radical cation (1(+*)) and anion (1(-*)), we report the UV-visible absorption spectra, and for neutral 1, also the magnetic circular dichroism (MCD) and the decomposition of the absorption spectrum into purely polarized components, deduced from fluorescence polarization. These results were used to identify a series of singlet excited states. For the first excited singlet and triplet states of 1, the transient visible absorption spectra, S(1) --> S(x) and sensitized T(1) --> T(x), and single exponential lifetimes, tau(F) = approximately 5.3 ns and tau(T) = approximately 200 micros, are reported. The spectra and lifetimes of S(1) --> S(0) fluorescence and sensitized T(1) --> T(x) absorption of 1 were obtained in a series of solvents, as was the fluorescence quantum yield, Phi(F) = 0.95-0.99. No phosphorescence has been detected. The first triplet excitation energy of solid 1 (11,400 cm(-1)) was obtained by electron energy loss spectroscopy, in agreement with previously reported solution values. The fluorescence excitation spectrum suggests an onset of a nonradiative channel at approximately 37,000 cm(-1). Excitation energies and relative transition intensities are in agreement with those of ab initio (CC2) calculations after an empirical 3000 cm(-1) adjustment of the initial state energy to correct differentially for a better quality description of the initial relative to the terminal state of an absorption transition. The interpretation of the MCD spectrum used the semiempirical PPP method, whose results for the S(0) --> S(x) spectrum require no empirical adjustment and are otherwise nearly identical with the CC2 results in all respects including the detailed nature of the electronic excitation. The ground state geometry of 1 was also calculated by the MP2, B3LYP, and CAS methods. The calculations provided a prediction of changes of molecular geometry upon excitation or ionization and permitted an interpretation of the spectra in terms of molecular orbitals involved. Computations suggest that 1 can exist as two nearly isoenergetic conformers of C(2) or C(s) symmetry. Linear dichroism measurements in stretched polyethylene provide evidence for their existence and show that they orient to different degrees, permitting a separation of their spectra in the region of the purely polarized first absorption band. Their excitation energies are nearly identical, but the Franck-Condon envelopes of their first transition differ to a surprising degree.