This dissertation thesis consists of a series of chapters that are interwoven by solving interesting biological problems, employing various computational methodologies. These techniques provide meaningful physical insights to promote the scientific fields of interest. Focus of chapter 1 concerns, the importance of computational tools like docking studies in advancing structure based drug design processes. This chapter also addresses the prime concerns like scoring functions, sampling algorithms and flexible docking studies that hamper the docking successes. Information about the different kinds of flexible dockings in terms of accuracy, time limitations and success studies are presented. Later the importance of Induced fit docking studies was explained in comparison to traditional MD simulations to predict the absolute binding modes. Chapter 2 and 3 focuses on understanding, how sickle cell disease progresses through the production of sickled hemoglobin and its effects on sickle cell patients. And how, hydroxyurea, the only FDA approved treatment of sickle cell disease acts to subside sickle cell effects. It is believed the primary mechanism of action is associated with the pharmacological elevation of nitric oxide in the blood, however, the exact details of this mechanism is still unclear. HU interacts with oxy and deoxyHb resulting in slow NO production rates. However, this did not correlate with the observed increase of NO concentrations in patients undergoing HU therapy. The discrepancy can be attributed to the interaction of HU competing with other heme based enzymes such as catalase and peroxidases. In these two chapters, we investigate the atomic level details of this process using a combination of flexible-ligand / flexible-receptor virtual screening (i.e. induced fit docking, IFD) coupled with energetic analysis that decomposes interaction energies at the atomic level. Using these tools we were able to elucidate the previously unknown substrate binding modes of a series of hydroxyurea analogs to human hemoglobin, catalase and the concomitant structural changes of the enzymes. Our results are consistent with kinetic and EPR measurements of hydroxyurea-hemoglobin reactions and a full mechanism is proposed that offers new insights into possibly improving substrate binding and/or reactivity. Finally in chapter 4, we have developed a 3D bioactive structure of O6-alkylguanine-DNA alkyltransferase (AGT), a DNA repair protein using Monte Carlo conformational search process. It is known that AGT prevents DNA damage, mutations and apoptosis arising from alkylated guanines. Various Benzyl guanine analouges of O6- methylguanine were tested for activity as potential inhibitors. The nature and position of the substitutions methyl and aminomethyl profoundly affected their activity. Molecular modeling of their interactions with alkyltransferase provided a molecular explanation for these results. The square of the correlation coefficient (R2 ) obtained between E-model scores (obtained from GLIDE XP/QPLD docking calculations) vs log(ED)values via a linear regression analysis was 0.96. The models indicate that the ortho-substitution causes a steric clash interfering with binding, whereas the meta-aminomethyl substitution allows an interaction of the amino group to generate an additional hydrogen bond with the protein. Using this model for virtually screening studies resulted in identification of seven lead compounds with novel scaffolds from National Cancer Institute Diversity Set2.

←Within this dissertation the topic of virtual screening is discussed with regard to three different cancer targets and also a brief introduction of the tools used in virtual screening. In Chapter 1, the reader will be introduced to virtual screening and the programs that are used in virtual screening. In Chapter 2, the first of three projects are discussed. This project consists of the work that was done to find inhibitors of the P53 binding domain of MDMX. In this project the mobility of residues within the binding site of MDMX are discussed and the ways in which we attempted to model how drugs would bind two adjacent pockets within MDMX. In Chapter 3, the virtual screening and modeling work done for RING domain of MDM2 and MDMX is discussed. This work was done in conjunction with Moffitt Cancer Center in order to solve the 60 year old mystery of the mechanism of how thalidomide and possibly its analog lenalidomide caused children to be born limbless. Current thinking is that Cereblon through an unknown teratogenic mechanism activates an increase in FGF8. We suggest a mechanism that may happen in parallel that involves stabilization of MDM2 and the reduction of P63 levels. Chapter 4, the work that was done against the BH3 binding domain of MCL-1 is discussed in conjunction with collaboration with the Manetsch lab. In order to complete this screening the validation of IC50 values and then attempt to modify those products based upon the structure of MCL-1. Chapter 5 discusses the work done to find inhibitors of deoxycytidine kinase. All of these chapters taken together provide a brief overview of the computational work done produce inhibitors of Protein-Protein Interaction against three major cancer targets.

In the design of novel materials, tunable properties are parameters such as composition or structure that may be adjusted in order to enhance a desired chemical or material property. Trends in tunable properties can be accurately predicted using computational and combinatorial chemistry tools in order to optimize a desired property. I present a study of tunable properties in materials and employ a variety of algorithms that ranges from simple screening to machine learning. In the case of tuning a nanocomposite membrane for olefin/paraffin separations, I demonstrate a rational design approach based on statistical modeling followed by ab initio modeling of the interaction of olefins with various nanoparticles. My simplified model of gases diffusing on a heterogeneous lattice identifies the conditions necessary for optimal selectivity of olefins over paraffins. The ab initio modeling is then applied to identify realistic nanomaterials that will produce such conditions. The second case, [alpha]-Fe₂O₃, commonly known as hematite, is potential solar cell material. I demonstrate the use of a screened search through chemical compound space in order to identify doped hematite-based materials with an ideal band gap for maximum solar absorption. The electronic structure of hematite is poorly treated by standard density functional theory and requires the application of Hartree-Fock exchange in order to reproduce the experimental band gap. Using this approach, several potential solar cell materials are identified based on the behavior of the dopants within the overall hematite structure. The final aspect of this work is a new method for identifying low-energy chemical processes in condensed phase materials. The gap between timescales that are attainable with standard molecular dynamics and the processes that evolve on a human timescale presents a challenge for modeling the behavior of materials. This problem is particularly severe in the case of condensed phase systems where the reaction mechanisms may be highly complicated or completely unknown. I demonstrate the use of support vector machines, a machine-learning technique, to create transition state theory dividing surfaces without a priori information about the reaction coordinate. This method can be applied to modeling the stability of novel materials. / text

The theoretical description of bistable materials requires dealing with the interplay of various phenomena, like temperature, environmental effects and electron correlation. We developed a procedure to combine the benefits of the molecular dynamics techniques with the accuracy of the ab initio wave function based methods including various models for the surroundings. The combination of these computational methods involved the making of specific software tools. The proposed procedure has been applied successfully, obtaining good agreements with experimental data, on organic molecules in solvent (cytosine tautomers in water), crystalline materials (NiO, LaMnO3 and TTTA) and inorganic spin-crossover compounds (FeII(bpy)3). We achieved a significant improvement in the description of their absorption spectra: including ligand-to-metal and metal-to-metal charge transfer processes, formally dipole forbidden transitions and the broadening of the spectral bands. Moreover, we observe dramatic changes on the electronic structure by incorporating the environmental effects on the theoretical model. / La descripció teòrica de materials biestables requereix el tractament de diversos fenòmens interactuants, com la temperatura, els efectes del medi i la correlació electrònica. S'ha desenvolupat un procediment que combina els beneficis de la dinàmica molecular amb la precisió dels mètodes ab initio basats en la funció d'ona incloent diferents models de l'entorn. La combinació d'aquests mètodes computacionals ha involucrat la creació de programari específic. El procediment proposat ha estat aplicat amb èxit, obtenint bona concordança amb els experiments, a molècules orgàniques en solvent (citosina en aigua), materials cristal•lins (NiO, LaMnO3 i TTTA) i compostos spin-crossover inorgànics (FeII(bpy)3). S'ha assolit una millora significativa en la descripció del seus espectres d'absorció: incloent la transferència de càrrega lligand-metall i metall-metall, les transicions formalment prohibides per dipol i l'eixamplament de les bandes espectrals. A més, s'observen canvis importants en l'estructura electrònica al incorporar els efectes de l'entorn en el model teòric.

Density-functional theory has become an indispensible tool for studying matter on the atomic level, being routinely applied across diverse disciplines from solid-state physics to chemistry and molecular biology. Its failure to account for dispersion interactions has spurred intensive research over the past decade. In this thesis, a semilocal density-functional approximation including dispersion is developed by combining standard functionals for exchange and correlation with the nonempirical “exchange-hole dipole moment“ (XDM) dispersion model of Becke and Johnson. With a minimum of empiricism, the method accurately describes all types of noncovalent interactions, from the extremely weak dispersion forces in rare-gas systems to the hydrogen bonding and stacking interactions responsible for the structure and function of biological macromolecules such as DNA and proteins. The method is compatible with a wide variety of standard Gaussian basis sets, and is easily applied to any system that can be modeled with density-functional theory.

Data is presented for a range of experiments that have been performed using a selected ion flow tube (SIFT) instrument operated at room temperature (~ 298K) with carrier gas pressures typically in the range of 0.3 – 0.6 Torr. The majority of the experiments discussed are performed on a Voice100 instrument that has not been described in detail previously. The Voice100 is a novel instrument that has been designed particularly for quantitative trace gas analysis using the SIFT-MS technique. A mixture of helium and argon carrier gases are employed in the Voice100 flow tube. By mixing carrier gases, the flow dynamics and diffusion characteristics of a flow tube are altered when compared to classic single carrier gas models. Therefore firstly, optimal flow conditions for the operation of a Voice100 are characterised. The diffusion of an ion in a mixture of carrier gases is then characterised using theoretical models and experimental techniques. This research requires that a new parameter Mp be defined regarding the mass discrimination of an ion in the non-field-free region near the downstream ion sampling orifice. Furthermore, a new method is described for the simultaneous measurement of rate coefficients for the reactions of H₃O⁺.(H₂O)n (n = 1, 2, 3) ions with analytes. Rate coefficients and branching ratios for the reactions of SIFT-MS precursor ions with specific analytes related to four individual applications are presented. For each application, the kinetic parameters are determined so as to facilitate the quantitative detection of the analytes relevant to that application. The GeoVOC application involves the measurement of hydrocarbon concentrations in the headspace of soil and water across a range of humidities. Alkyl esters are investigated to allow for the quantitative detection of each compound in fruits and vegetables. Chemical warfare agents, their surrogates and precursor compounds are studied which allows for the quantitative or semi-quantitative detection of a range of highly toxic compounds. Finally, 17 compounds classified by the US-EPA as hazardous air pollutants are studied that enables SIFT-MS instruments to replicate sections of the TO-14A and TO-15 methods.

To exemplify how theoretical chemistry can be applied to understand ground and excited state reactivity, four different chemical reactions have been modeled. The ground state chemical reactions are the simplest models in chemistry. To begin, a route to break down halomethanes through reactions with ground state cyano radical has been selected. Efficient explorations of the potential energy surfaces for these reactions have been carried out using the artificial force induced reaction algorithm. The large number of feasible pathways for reactions of this type, up to eleven, shows that these seemingly simple reactions can be quite complex. This exploration is followed by accurate quantum dynamics with reduced dimensionality for the reaction between Cl− and PH2Cl. The dynamics indicate that increasing the dimensionality of the model to at least two dimensions is a crucial step for an accurate calculation of the rate constant. After considering multiple pathways on a single potential energy surface, various feasible pathways on multiple surfaces have been investigated. As a prototype of these reactions, the thermal decomposition of a four-membered ring peroxide compound, called 1,2-dioxetane, which is the simplest model of chemi- and bioluminescence, has been studied. A detailed description of this model at the molecular level can give rise to a unified understanding of more complex chemiluminescence mechanisms. The results provide further details on the mechanisms and allow to rationalize the high ratio of triplet to singlet dissociation products. Finally, a thermal decomposition of another dioxetane-like compound, called Dewar dioxetane, has been investigated. This study allows to understand the effect of conjugated double bonds adjacent to the dioxetane moiety in the chemiluminescence mechanism of dioxetane. Our studies illustrate that no matter how complex a system is, theoretical chemistry can give a level of insight into chemical processes that cannot be obtained from other methods.

The nonlinear optical (NLO) properties were investigated in various extended　π-conjugated chromophores: cyanine and alkyne carbocations; porphyrin dimers; and squaraine compounds that possess electronic, double resonance, and vibronic based NLO properties. In summary: (i) It was demonstrated that the alkyne carbocations have very similar optical properties to traditional cyanine dyes. Our theoretical results establish that the alkyne carbocations, in spite of their significant degree of bond-length alternation, behave in the same way as cyanine dyes. (ii) The nature of the -bridge in porphyrin dimers tunes the electronic coupling strength, which in turn determines the splitting of the energy levels and the (non)linear optical properties. (iii) We have shown that the origin of the lowest TPA-active states in squaraines is dependent on the nature of substituent donor moiety, changing from predominantly electronic to vibronic in character. For all squaraines containing indolinylidenemethyl donors, a vibronic origin for the TPA peak, and the energy and lineshape of the experimentally observed lowest TPA peak in these compounds were confirmed.

This study concerns the synthesis, structure and reactivity of nitrosyl complexes of ruthenium and osmium. Attempts have been made to prepare coordinatively saturated and unsaturated complexes and a study of their oxidative addition reactions bears considerable resemblance to the more familiar carbonyl complexes M(CO)3(PPh3)2. A number of interesting atom transfer reactions, generally involving oxygen, have been observed. The d8 complex RuCl(CO)(NO)(PPh3)2 results from the interaction of RuHCl(CO)(PPh3)3 with N-methyl-N-nitrosotoluene-p-sulphonamide. The labile halide ligand is readily displaced by a large range of anions and it is believed that both linear and bent nitrosyl linkages may exist for different members of this series. The structures of these complexes are discussed in the light of recent X-ray crystal structure data. Halogens and hydrogen halides add to give the familiar RuX3(NO)(PPh3)2; RuCl3(NO)(PPh2Me)2 is prepared in a direct reaction and also by phosphine exchange and 1H n.m.r. data confirm that the phosphine ligands are trans. The complexes RuX(CO)(NO)(PPh3)2 react readily with O2 to form the dioxygen complexes Ru(O2)X(NO)(PPh3)2. Halogens and hydrogen halides produce RuX3(NO)(PPh3)2. The dioxygen complexes react with SO2 and N2O4 to give sulphato and dinitrato complexes respectively. The reaction with CO results in the intramolecular oxidation of the nitrosyl group to coordinated nitrate accompanied by the incorporation of two moles of CO, i.e. RuX(NO3)(CO)2(PPh3)2 is formed. The dioxygen complexes catalytically oxidise triphenylphosphine or triphenylarsine to the respective oxides and RuX(NO)(PPh3)2 can be isolated from this cycle. Reactions of these four-coordinated complexes with O2, CO, Cl2 and NOBF4 are recorded. The dinitrosyl complex Ru(NO)2(PPh3)2 is reported from a number of syntheses, the most successful being via a ligand reaction when RuCl2(CO)2(PPh3)2 is heated with NaNO2 and Ph3P in dimethyl formamide. The P-tolyldiphenylphosphine analogue is also reported and the mono-substituted product Ru(NO)2(PPh3)[P(OPh)3] is produced in an exchange reaction between Ru(NO)2(PPh3)2 and excess triphenylphosphite. This phosphite complex reacts with Ph3P and O2 to produce Ru(O2)(NO2)(NO)PPh3)2 by an atom transfer process. Ru(NO)2(PPh3)2 reacts with the acids HY (Y = BF4, PF6, ClO4) and O2 to give the dinitrosyl cations [Ru(OH)(NO)2(PPh3)2]+Y- in which the two nitrosyl groups are structurally and electronically inequivalent. [RuCl(NO)2(PPh3)2]BF4 is reported and reactions of these dinitrosyl cations with halide ions to give RuX2(NO3)(NO)(PPh3)2, with intramolecular oxidation of the NO group, are also described. OsCl2(OH)(NO)(PPh3)2 reacts irreversibly with alcohols to form OsCl2(OR)(NO)(PPh3)2 (R = CH3, C2H5, n-C3H7, (CH3O)CH2CH2) which readily undergo hydride abstraction to form OsHCl2(NO)(PPh3)2. Sodium borohydride converts this complex to the trihydrido species OsH3(NO)(PPh3)2 and if the reaction is performed in the presence of Ph3P, OsH(NO)(PPh3)3 results. The coordinated perchlorate complex OsHCl(OClO3)(NO)(PPh3)2 results form the reaction of OsHCl2(NO)(PPh3)2 with silver perchlorate; this is readily reversed by chloride ions or the solvents CH2Cl2 and CHCl3. This perchlorato complex also arises from the reaction of OsH(CO)(NO)(PPh3)2 with HClO4 and a related tetrafluoroborato complex, OsH(OC2H5)(FBF3)(NO)(PPh3)2 by substituting HBF4. This complex reacts with Ph3P to give [OsH(OH)(NO)(PPh3)3]BF4, CO to give [Os(CO)2(NO)(PPh3)2]BF4 and LiX (X = Br, I) to give OsHX2(NO)(PPh3)2. OsHCl(OClO3)(NO)(PPh3)2 reacts with NaOH in methanol, in the presence of O2 to produce Os(O2)Cl(NO)(PPh3)2. This dioxygen complex is far less stable than the ruthenium analogue but it undergoes similar reactions. Ph3P is oxidised, SO2 and CO give sulphato and a nitratodicarbonyl complex respectively. Infra-red, 1H n.m.r., conductivity, molecular weight data and elemental analysis have been used in formulation and structural assignment.

This study concerns the synthesis, structure and reactivity of nitrosyl complexes of ruthenium and osmium. Attempts have been made to prepare coordinatively saturated and unsaturated complexes and a study of their oxidative addition reactions bears considerable resemblance to the more familiar carbonyl complexes M(CO)3(PPh3)2. A number of interesting atom transfer reactions, generally involving oxygen, have been observed. The d8 complex RuCl(CO)(NO)(PPh3)2 results from the interaction of RuHCl(CO)(PPh3)3 with N-methyl-N-nitrosotoluene-p-sulphonamide. The labile halide ligand is readily displaced by a large range of anions and it is believed that both linear and bent nitrosyl linkages may exist for different members of this series. The structures of these complexes are discussed in the light of recent X-ray crystal structure data. Halogens and hydrogen halides add to give the familiar RuX3(NO)(PPh3)2; RuCl3(NO)(PPh2Me)2 is prepared in a direct reaction and also by phosphine exchange and 1H n.m.r. data confirm that the phosphine ligands are trans. The complexes RuX(CO)(NO)(PPh3)2 react readily with O2 to form the dioxygen complexes Ru(O2)X(NO)(PPh3)2. Halogens and hydrogen halides produce RuX3(NO)(PPh3)2. The dioxygen complexes react with SO2 and N2O4 to give sulphato and dinitrato complexes respectively. The reaction with CO results in the intramolecular oxidation of the nitrosyl group to coordinated nitrate accompanied by the incorporation of two moles of CO, i.e. RuX(NO3)(CO)2(PPh3)2 is formed. The dioxygen complexes catalytically oxidise triphenylphosphine or triphenylarsine to the respective oxides and RuX(NO)(PPh3)2 can be isolated from this cycle. Reactions of these four-coordinated complexes with O2, CO, Cl2 and NOBF4 are recorded. The dinitrosyl complex Ru(NO)2(PPh3)2 is reported from a number of syntheses, the most successful being via a ligand reaction when RuCl2(CO)2(PPh3)2 is heated with NaNO2 and Ph3P in dimethyl formamide. The P-tolyldiphenylphosphine analogue is also reported and the mono-substituted product Ru(NO)2(PPh3)[P(OPh)3] is produced in an exchange reaction between Ru(NO)2(PPh3)2 and excess triphenylphosphite. This phosphite complex reacts with Ph3P and O2 to produce Ru(O2)(NO2)(NO)PPh3)2 by an atom transfer process. Ru(NO)2(PPh3)2 reacts with the acids HY (Y = BF4, PF6, ClO4) and O2 to give the dinitrosyl cations [Ru(OH)(NO)2(PPh3)2]+Y- in which the two nitrosyl groups are structurally and electronically inequivalent. [RuCl(NO)2(PPh3)2]BF4 is reported and reactions of these dinitrosyl cations with halide ions to give RuX2(NO3)(NO)(PPh3)2, with intramolecular oxidation of the NO group, are also described. OsCl2(OH)(NO)(PPh3)2 reacts irreversibly with alcohols to form OsCl2(OR)(NO)(PPh3)2 (R = CH3, C2H5, n-C3H7, (CH3O)CH2CH2) which readily undergo hydride abstraction to form OsHCl2(NO)(PPh3)2. Sodium borohydride converts this complex to the trihydrido species OsH3(NO)(PPh3)2 and if the reaction is performed in the presence of Ph3P, OsH(NO)(PPh3)3 results. The coordinated perchlorate complex OsHCl(OClO3)(NO)(PPh3)2 results form the reaction of OsHCl2(NO)(PPh3)2 with silver perchlorate; this is readily reversed by chloride ions or the solvents CH2Cl2 and CHCl3. This perchlorato complex also arises from the reaction of OsH(CO)(NO)(PPh3)2 with HClO4 and a related tetrafluoroborato complex, OsH(OC2H5)(FBF3)(NO)(PPh3)2 by substituting HBF4. This complex reacts with Ph3P to give [OsH(OH)(NO)(PPh3)3]BF4, CO to give [Os(CO)2(NO)(PPh3)2]BF4 and LiX (X = Br, I) to give OsHX2(NO)(PPh3)2. OsHCl(OClO3)(NO)(PPh3)2 reacts with NaOH in methanol, in the presence of O2 to produce Os(O2)Cl(NO)(PPh3)2. This dioxygen complex is far less stable than the ruthenium analogue but it undergoes similar reactions. Ph3P is oxidised, SO2 and CO give sulphato and a nitratodicarbonyl complex respectively. Infra-red, 1H n.m.r., conductivity, molecular weight data and elemental analysis have been used in formulation and structural assignment.