Molecular modelling has become a well-established tool for studying biological mole- cules, moreover with the prospect of being useful for drug development. The thesis summarises research on the methodological advances in the treatment of molecular flexibility and intermolecular interactions. Altogether, seven original publications are accompanied by a text which aims to provide a general introduction to the topic as well as to emphasise some consequences of the computer-aided drug design. The molecular flexibility is tackled by a study of a drug-DNA interaction and also by an investigation of small drug molecules in the context of implicit solvent models. The approaches which neglect the conformational freedom are probed and compared with experiment in order to suggest later, how to cope with such a freedom if in- evitable. The noncovalent interactions involving halogen atoms and their importance for drug development are briefly introduced. Finally, a model for a faithful description of halogen bonds in the framework of molecular mechanics is developed and its per- formance and limits are tested by a comparison with benchmark ab initio calculations and experimental data. 1

This study reports on the synthesis of N-doped carbon spheres (N-CSs) by a simple synthetic procedure. A horizontal CVD type reactor was used to synthesize N-CSs from pyridine. Depending on the dilution of the pyridine with toluene, a nitrogen content of 0.13-5 mol % was obtained. The use of a vertical CVD reactor gave N-CSs with a N-content of 0.19-3 mol % when an ammonium solution and acetylene were used as reactants. The diameters of carbon spheres were found to be in the range of 40 nm to 1000 nm for both CVD reactors. The diameter can be controlled by varying the flow rate, temperature, time, concentration and the reactor type. The samples were characterized by TEM, HRTEM, elemental analysis, Raman spectroscopy, TGA, PXRD and ESR. We have demonstrated that unsubstituted thiophene can be polymerized by Fe3+-catalyzed oxidative polymerization. The average particle size was about 50 nm, within a narrow particlesize distribution. The undoped carbon spheres (CSs) were reacted with thiophene to give polymer/carbon composites containing polythiophene and carbon nanospheres via chemical oxidative polymerization reaction. Polythiophene molecules were either chemically bonded or physically adsorbed to the surface of carbon spheres. The microstructure and properties of the two types of composites were compared. The thermogravimetric analysis data confirmed that the presence of CSs in the polymer\carbon composites is responsible for the higher thermal stability of the composite material in comparison with pristine polythiophene. The FTIR analysis showed that covalent functionalized nanocomposites exhibit a high intensity of a C-S bond This study reports on the synthesis of N-doped carbon spheres (N-CSs) by a simple synthetic procedure. A horizontal CVD type reactor was used to synthesize N-CSs from pyridine. Depending on the dilution of the pyridine with toluene, a nitrogen content of 0.13-5 mol % was obtained. The use of a vertical CVD reactor gave N-CSs with a N-content of 0.19-3 mol % when an ammonium solution and acetylene were used as reactants. The diameters of carbon spheres were found to be in the range of 40 nm to 1000 nm for both CVD reactors. The diameter can be controlled by varying the flow rate, temperature, time, concentration and the reactor type. The samples were characterized by TEM, HRTEM, elemental analysis, Raman spectroscopy, TGA, PXRD and ESR. We have demonstrated that unsubstituted thiophene can be polymerized by Fe3+-catalyzed oxidative polymerization. The average particle size was about 50 nm, within a narrow particlesize distribution. The undoped carbon spheres (CSs) were reacted with thiophene to give polymer/carbon composites containing polythiophene and carbon nanospheres via chemical oxidative polymerization reaction. Polythiophene molecules were either chemically bonded or physically adsorbed to the surface of carbon spheres. The microstructure and properties of the two types of composites were compared. The thermogravimetric analysis data confirmed that the presence of CSs in the polymer\carbon composites is responsible for the higher thermal stability of the composite material in comparison with pristine polythiophene. The FTIR analysis showed that covalent functionalized nanocomposites exhibit a high intensity of a C-S bondThis study reports on the synthesis of N-doped carbon spheres (N-CSs) by a simple synthetic procedure. A horizontal CVD type reactor was used to synthesize N-CSs from pyridine. Depending on the dilution of the pyridine with toluene, a nitrogen content of 0.13-5 mol % was obtained. The use of a vertical CVD reactor gave N-CSs with a N-content of 0.19-3 mol % when an ammonium solution and acetylene were used as reactants. The diameters of carbon spheres were found to be in the range of 40 nm to 1000 nm for both CVD reactors. The diameter can be controlled by varying the flow rate, temperature, time, concentration and the reactor type. The samples were characterized by TEM, HRTEM, elemental analysis, Raman spectroscopy, TGA, PXRD and ESR. We have demonstrated that unsubstituted thiophene can be polymerized by Fe3+-catalyzed oxidative polymerization. The average particle size was about 50 nm, within a narrow particlesize distribution. The undoped carbon spheres (CSs) were reacted with thiophene to give polymer/carbon composites containing polythiophene and carbon nanospheres via chemical oxidative polymerization reaction. Polythiophene molecules were either chemically bonded or physically adsorbed to the surface of carbon spheres. The microstructure and properties of the two types of composites were compared. The thermogravimetric analysis data confirmed that the presence of CSs in the polymer\carbon composites is responsible for the higher thermal stability of the composite material in comparison with pristine polythiophene. The FTIR analysis showed that covalent functionalized nanocomposites exhibit a high intensity of a C-S bond at 695 cm-1 , which is not observed in the noncovalent functionalized nanocomposites

Design and synthesis of novel supramolecular architectures is an interesting area of research in the last two decades. Intermolecular interactions assisted self-assembly of molecular and macromolecular building blocks play an important role in obtaining the desired shape and function of the supramolecular architectures. A combination of the classical covalent synthesis with the self-assembly assisted formation of well-defined architectures (noncovalent synthesis) allows us to develop novel multifunctional materials. Our approach in this area is focused on the design of novel molecular and biomolecular building blocks and the optimization of structure-property relationship of the materials using self-assembly approach. This presentation will focus on our recent efforts on the design and synthesis of polymers and oligopeptides for investigation of the self-assembly and fine-tuning the structure-property relationship. Also, some highlights will be given on our initial investigation on how hard minerals are synthesized by natural molecules through the self-assembly processes. / Singapore-MIT Alliance (SMA)

The sensitivity of biological studies performed between 190 and 650 nm is greatly reduced due to the autofluorescence of biomolecules and impurities in this region. Therefore, the enhanced signal-to-noise ratios encountered at longer wavelengths makes biological analysis within the near infrared (NIR) region from 650 nm to 1100 nm far more advantageous. This dissertation describes the noncovalent binding interactions of near-infrared (NIR) carbocyanine dyes with human serum albumin (HSA) and poly-L-lysine (PLL) using UV-Vis/NIR absorption spectroscopy, emission spectroscopy, circular dichroism (CD), and fluorescence detected circular dichroism (FDCD). The optical spectroscopy methods used in this work are described in detail in Chapter 1. The various applications of NIR dyes in protein analysis are introduced in Chapter 2. In general, the sensitivity of cyanines to the polarity of their local environment makes them quite suitable for protein labeling schemes. In aqueous media, cyanines have a high propensity for self-association. Yet in the hydrophobic binding sites of globular proteins, these aggregates often dissipate. Absorption and emission spectroscopy can be utilized to observe the differential spectral properties of monomer, intra-molecular and intermolecular aggregates. In Chapter 3, the photophysical properties of bis(cyanine) NIR dyes containing di-, tri-, and tetraethylene glycol linkers were each examined in the presence of HSA are discussed. Variations in chain length as well as probe flexibility were demonstrated through distinct differences in absorption and emission spectra. The observed changes in the spectral properties of the NIR dyes in the presence and absence of HSA were correlated to the physical parameters of the probes' local environment (i.e., protein binding sites and self-association). All three bis-cyanines examined exhibited enhanced fluorescence in the presence of HSA. The bis-cyanine dye containing the tri(ethylene glycol) spacer allowed for a complete overlap of the benzene rings, to form π-π interactions which were observed as intra-molecular H-aggregate bands. The dye exhibited no fluorescence in buffer, owing to the H-aggregation observed in the absorption data. In the presence of HSA, the intra-molecular dimers were disrupted and fluorescence was then detected. The "cut-on" fluorescence displayed by the dye in the presence of HSA made it ideal for noncovalent labeling applications. The utility of several NIR dyes for use as secondary structural probes was investigated in Chapter 4. NIR dyes were screened thoroughly using UV-Vis/NIR absorption spectroscopy dyes with spectral properties which were sensitive to protein secondary structure models of such as PLL in basic solution. Two NIR dyes were found to be quite sensitive to the structural features of uncharged α- and β-PLL. The chiral discrimination of these probes for basic protein secondary structures was also evaluated through CD measurements within the NIR probes' absorption bands.

Computational chemists are concerned about two aspects when choosing between the myriad of theoretical methodologies: the accuracy (the "truth") and the computational cost (the tractability). Among the least expensive methods are the Hartree-Fock (HF), density functional theory (DFT), and second-order Moller-Plesset perturbation theory (MP2) methods. While each of these methods yield excellent results in many cases, the inadequate inclusion of certain types of electron correlation (either high-orders or nondynamical) can produce erroneous results. The compromise for the computation of noncovalent interactions often comes from empirically scaling DFT and/or MP2 methods to fit benchmark data sets. The DFT method with an empirically fit dispersion term (DFT-D) often yields semi-quantitative results. The spin-component scaled MP2 (SCS-MP2) method parameterizes the same- and opposite-spin correlation energies and often yields less than 20% error for prototype noncovalent systems compared to chemically accurate CCSD(T) results. There is no simple fix for cases with a large degree of nondynamical correlation (such as transition metal-salen complexes). While testing standard and new DFT functionals on the spin-state energy gaps of transition metal-salen complexes, no DFT method produced reliable results compared to very robust CASPT3 results. Therefore each metal-salen complex must be evaluated on a case-by-case basis to determine which methods are the most reliable. Utilizing a combination of DFT-D and SCS-MP2 methods, the reaction mechanism for the addition of cyanide to unsaturated imides catalyzed by the Al(Cl)-salen complex was performed. Various experimental observations are rationalized through this mechanism.

"Multi-functionalized Side-chain Supramolecular Polymers:A Methodology Towards Tunable Functional Materials". Even as we see a significant growth in the field of side-chain supramolecular polymers in the last ten years, systems employing multiple non-covalent interactions have been scarcely studied. Non-covalent multi-functionalization provides unique advantages such as rapid optimization via reversible functionalization as well as for the tuning of materials properties by exploiting the differences in the nature of these reversible interactions. This thesis involves the design principles, synthesis & methodology of side-chain multi-functionalized polymers. The combination of the principles of a functionally tolerant & a controlled polymerization technique such as ROMP with multiple noncovalent interactions such as hydrogen bonding, metal coordination & Coulombic self-assembly has been used to synthesize multi-functionalized polymers. Furthermore, the orthogonality between hydrogen bonding, metal coordination & ionic self-assembly in random/block copolymers has been studied in detail. In order to validate the viability of this multi-functionalization methodology towards materials design non-covalent crosslinking of polymers was used as a potential application. Three classes of crosslinked networks have been studied: complementary multiple-hydrogen bonded networks, multiple-metal crosslinked networks, & multi-functionalized hydrogen bonded & metal coordinated networks. By using non-covalent multi-functionalization, important materials properties & its responsiveness towards chemical agents have been tuned & controlled to yield novel materials which would be difficult to be obtained via traditional covalent techniques or by using single non-covalent interactions.

Noncovalent interactions in complex chemical systems are examined by considering model systems which capture the essential physics of the interactions and applying correlated electronic structure techniques to these systems. Noncovalent interactions are critical to understanding a host of energetic and structural properties in complex chemical systems, from base pair stacking in DNA to protein folding in organic solids. Complex chemical and biophysical systems, such as enzymes and proteins, are too large to be studied using computational techniques rigorous enough to capture the subtleties of noncovalent interactions. Thus, the larger chemical system must be truncated to a smaller model system to which rigorous methods can be applied in order to capture the essential physics of the interaction. Computational methodologies which can account for high levels of electron correlation, such as second-order perturbation theory and coupled-cluster theory, must be used. These computational techniques will be used to study several types (pi stacking, S/pi, and C-H/pi) of noncovalent interactions in two chemical contexts: biophysical systems and organic solids.

The theoretical part of the Master´s thesis describes ab initio methods in quantum chemistry and semiempirical methods, which represents a way in overcoming of main disadvantages in ab initio methods (costs, speed). The experimental part was focused on comparison highly accurate CCSD(T) method with used semiempirical methods (AM1, PM3, PM6, and PM7). The data were mostly compared on small model systems with ions, which are an essential part of many biological systems. Furthermore, the applicability of semiempirical methods was examined for the description of intra- and intermolecular hydrogen bonds and van der Waals interactions.

Les polyphénols sont abondamment trouvés dans de nombreux fruits, légumes, boissons etc. et ils possèdent de nombreux effets bénéfiques pour la santé. Les méthodes de calcul ont été utilisées dans le cadre de cette thèse pour rationaliser, décrire et prédire les propriétés physiques et chimiques des flavonolignanes et des pyranoanthocyanines pour la compréhension de leurs actions biologiques au niveau moléculaire. Tous les résultats des calculs théoriques ont été discutés par rapport aux données expérimentales. Les propriétés liées à l'activité antioxydante des flavonolignanes ont été étudiées par les méthodes de la théorie de la densité fonctionnelle (DFT). La dépendance au pH des propriétés d'absorption UV/Vis des flavonolignanes et des pyranoanthocyanines ont été évaluée par des méthodes DFT dépendante du temps (TD-), et les interactions non-covalentes ont été étudiées avec les méthodes de DFT incluant la correction de dispersion. Un bref aperçu est également donné sur l'interaction de ces composés avec des biomolécules. Le chapitre 6 présente des résultats non encore publiés de plusieurs systèmes non-covalents pigment: copigment. Cette partie des résultats constitue un bon point de départ pour la recherche du ‘meilleur copigment’. / Polyphenols are abundantly found in many fruit, vegetables, beverages, etc. and they possess many potential health benefits. Computational methods were thoroughly used through this thesis to rationalize, describe and predict physical chemical properties of flavonolignans and pyranoanthocyanins. Here, we aim at an understanding of polyphenol biological actions at a molecular level. All outcomes from the theoretical computations were discussed with respect to experimental data. The properties related to antioxidant activity of flavonolignans were investigated by density functional theory (DFT) methods. The pH dependence of ultraviolet/visible (UV/Vis) absorption properties of flavonolignans and pyranoanthocyanins were evaluated by time dependent (TD-) DFT methods, and noncovalent interactions were investigated within dispersion-corrected DFT methods. A short overview is also given on interaction of such compounds with biomolecules. Chapter 6 presents yet not published results of several noncovalent pigment: copigment systems. This part of the results serves as a good starting point to search for ‘the best copigment’.

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