Ab initio Quantum Chemistry Methods for Modeling Molecular Excited States Beyond Configuration Interaction Singles

Electron transfer and energy transfer play a central role in photo-induced excited state chemical dynamics and are critical for understanding the fundamental processes in photosynthesis. Understanding electron and energy transfer at the molecular level is essential, since they must compete with deactivation processes back to the molecular ground state-- and deactivation releases any captured energies as wasted heat. Modeling electronic relaxation process is very challenging, however, for 2 reasons: i) Obtaining accurate potential energy surfaces (PESs) by solving the electronic Hamiltonian (only) is nontrivial, since all electrons are coupled together, which is essentially a many-body problem. It is even more difficult in the context of photochemistry, where the relevant molecules are typically big; ii) The Born-Oppenheimer Approximation of separating electronic and nuclear motion may be invalid, and thus one has to model nonadiabatic dynamics. This thesis is focused on the first problem above, i.e. solving the electronic Hamiltonian, where there is currently a lack of effective ab initio quantum chemistry methods, especially in the presence of charge transfer (CT) states. Historically Configuration Interaction Singles (CIS) has been the standard method for modeling electronic excited states with qualitatively correct wavefunctions, but CIS is highly biased against charge transfer states-- which are very important for modeling photo-induced relaxation. Nevertheless, in this thesis, CIS proves to be a good starting point for improved ab initio quantum chemistry methods, that build in the correct molecular orbital optimization. These algorithms are labeled as: i) Orbital Optimized Configuration Interaction Singles (OO-CIS), ii) Variational Orbital Adapted Configuration Interaction Singles (VOA-CIS), and iii) Fully Variational Orbital Adapted Configuration Interaction Singles (FVOA-CIS). Each of the three algorithms above represents an improvement upon its predecessor. i) OOCIS is able to recover perturbative corrections for CT states; ii) its variational extension VOA-CIS proves to be very effective for constructing globally smooth adiabatic PESs even with CT states; and iii) because it is fully variational, FVOA-CIS PESs are so smooth that it should allow analytic gradients. We believe these approaches will be widely used for future accurate electronic structure calculations

An extracellular drug binding site of potassium channels THIK-1 and THIK-2

Background: THIK-1, THIK-2 and TREK-1 and all belong to family of two-pore-domain potassium channel (K2P channels). THIK-2 was until recently regarded as ‘silent’ potassium channels. 3-isobutyl-1-methylxanthine (IBMX) is normally used as inhibitor of phosphodiesterase, resulting in an increase of cAMP levels in the cytosol. Aims: Identification of an extracellular drug binding site on THIK-1 and THIK-2. Methods: Whole cell recording patch clamp measurements in mammalian cells was used to analyze K2P channels mentioned above. Chemicals such as IBMX, forskolin and cAMP were used intracellularly (via the pipette solution) and/or extracellularly (via the bath solution). To identify the binding site of IBMX on THIK-1 we mutated all amino acids of the helical cap one by one and screened for changes in IBMX sensitivity of the channels. To analyze the surface expression of the channel we used HA-tagged THIK-2 and thus quantified the copy number of the channels at the cell membrane using an antibody-based assay. Results: We found that IBMX can rapidly inhibit both the inward and outward currents carried by THIK-1 channels; the IC50 of this effect was about 120 μM. The application of H89 (PKA inhibitor) and forskolin (PKA activator) did not modify the effects of IBMX on the channel. Application of 100 μM intracellular cAMP almost completely inhibited TREK-1 current but not THIK-1 current, indicating that the effect of IBMX in THIK-1 is not mediated by cAMP. Finally, we found that IBMX blocks THIK-1 currents only if it is applied extracellularly. By mutating all of the helical cap amino acids, we found that the arginine to alanine mutant of THIK-1 (THIK-1R92A) had a lower sensitivity to IBMX. Mutation of the arginine at position 92 to glutamate or glutamine reduced the sensitivity to IBMX even further. R92 is localized to the linker region between cap helix 2 (C2) and the pore helix (P1). Part of the linker region is not visible in the crystal structures. R92 is at the end of the unstructured region.Compared to THIK-1, the 'silent' channel THIK-2 has an additional domain at its N-terminus (residues 6-24) which contains a putative retention signal (RRR). Removal of this additional domain (mutant THIK-2Δ6-24) or mutation of the RRR motif to AAA (THIK-2AAA mutant) gave rise to a measurable potassium current. Furthermore, the surface expression of the reporter protein CD74 containing the AAA mutated N-terminus of THIK-2 was more than threefold larger than the analogous reporter protein containing the wild type N-terminus of THIK-2 (RRR). These data indicate that the ER retention/retrieval signal RRR can prevent the THIK-2 export to the cell membrane, leading to the silence of the channel. In addition, we found that THIK-2 currents can also be blocked by application of IBMX from the extracellular side. Conclusions: IMBX can block TREK-1 channels though the PKA pathway, it also can bind to the extracellular side of THIK-1 or THIK-2, leading to a direct block of the channels. This describes a novel effect of IBXM on K2P channels. The IC50 of the direct effect of IBMX on THIK-1 channels was about 120 μM. Our results suggest that arginine 92 of THIK-1 and the C2-P1 linker region of K2P channels play an important role in the binding of IBMX, and perhaps other more potent drugs, to the channel

Active sites engineering of metal-organic frameworks for heterogeneous catalysis

With the depletion of fossil fuels and global energy crisis confronting us, there is a pressing need for developing economically, environmentally benign and efficient processes in catalytic reactions for chemical synthesis. In comparison to homogeneous catalysis, which is hurdled by metal contamination and limited recyclability, heterogeneous catalysis, which holds multiple advantages of facile separation, recyclability and potential in continues flow reaction systems, is promptly developing field in chemical manufacturing nowadays. Since the first catalytic applications of MOFs reported by Fujita and coworkers in 1994, the use of MOFs in heterogeneous catalysis is under intense investigation. From viewpoint of catalysis, the high design versatility of MOFs renders unparalleled advantages for their applications in catalysis, since it is feasible to rationally engineer not only the active sites but also its chemical environment at the atomic level. Furthermore, the ultrahigh surface area/porosity and periodical structures of MOFs is beneficial to the transportation of reactants/products and guarantee the accessibility of active sites, leading to high activity in catalysis. In principle, the catalytic sites in MOFs can be divided by several categories. 1) The organic linker and the inorganic nodes, which can be induced by direct synthesis or post-synthetic modification; 2) The inner pores of the MOFs can serve as scaffold in which the catalytic species (e.g., metal or metal oxide nanoparticle, metal complex, etc.) is encapsulated;3) The pyrolysis of MOFs to porous carbon or metal/carbon hybrid composites is prone to preserve the merits of MOFs and demonstrate huge potential in heterogeneous and electrochemical catalysis In this dissertation, I present several design of heterogeneous catalysts for desired/model catalytic reactions via active sites engineering in MOFs, that is, using MOFs as scaffold for noble metal NPs and heterogenization of organometallic species and explore its application in catalytic organic transformations; using MOFs as sacrificial templates to prepare monodisperse thiolated Pd NCs or to afford porous carbons with Lewis base sites and investigate its catalytic performance in heterogeneous catalysis. By virtue of MOFs’ tunability, versatility, and flexibility, the rationally-designed MOF catalysts exhibited excellent catalytic performance in tandem catalysis and established a clear structure-activity relationship in the heterogeneous catalysis. Future work on exploring novel and efficient tandem catalysis and elucidate the underlying mechanism of linker engineering in heterogeneous MOFs catalysis in currently undergoing