The chemistry of the enzyme glutathione peroxidase and synthetic organoselenium enzyme mimics has been a significant research interest for more than three decades. In this work, the results of a computational study employing modern electronic structure methods to model the reactions of a synthetic glutathione peroxidase mimic are presented. The ability of nine density-functional theory methods and thirteen basis sets to predict both molecular geometries and bond dissociation energies in organoselenium compounds is examined. This is used to determine the best methodology to employ for the study of glutathione peroxidase mimics. The key reactions in the catalytic mechanism of the organoselenium antioxidant N,N-dimethyl-benzylamine-2-selenol are the focus of the remainder of the document. This is a three-step mechanism which includes many of the organic forms adopted by selenium compounds, including selenol, oxoacids, and selenylsulfides. In the first step of the cycle, the well-studied reduction of hydrogen peroxide by a selenol and a diselenide is modelled. The second step modelled is a substitution reaction at the selenium centre of a selenenic acid with a thiol. The final step discussed is the reduction of the selenium centre in a selenylsulfide, regenerating the selenol and forming a disulfide species. Each mechanism is evaluated by discussing both molecular geometries and reaction energetics. To close the document, the peroxide reduction reaction is revisited to determine the effects of substitution on the phenyl ring of the synthetic antioxidant. This serves as a preliminary attempt to improve the antioxidant efficiency of this compound. In addition to a discussion of the changes in reaction energetics predicted, the topology of the electron density is studied using the quantum theory of atoms in molecules to better understand how the distribution of electron density is affected by substituents.

Sophisticated catalytically active sites of metalloenzymes provide inspiration to synthetic chemists, as the metal coordination environments are often atypical to those found on the chemist's benchtop. Furthermore, metal-ligand cooperativity using earthabundant metals is anticipated to eventually supplant noble metals, currently used in industrial catalysis. Despite progress in synthesis of small molecule active site models, reproduction of the enzymatic function is rarely observed. However, differences that might define catalytic efficiency of enzymes can be addressed by theory. Density functional theory, or DFT, has been developed as an in silico tool to complement and interpret crystallographic and spectroscopic results or to make predictions in the absence of experimental data. In this dissertation, such techniques serve to elucidate the observed reactivity or electronic character of both nickel and copper bound in square planar N₂S₂ ligand fields, and of {Fe(NO)₂} units, respectively. Nickel and copper complexes in tetraanionic N₂S₂⁴⁻ ligand environments were investigated with respect to change of metal, to modification of ligand environment, and to response in reactivity of thiolate sulfur atoms. From the DFT calculations and consistent with experimental observations, it was discovered that binding of a nucleophile at one thiolate sulfur effectively decreases reactivity of the second sulfur, and nucleophilic binding at both sulfurs serves to deactivate the complex toward further thiolate reactivity. Additionally, despite both Cu and Ni binding comfortably in the N₂S₂⁴⁻ coordination sphere, the former displays increased ionicity versus the latter, demonstrated by electrostatic potential mapping. A methodology for accurate modeling of geometry and vibrational frequencies of complexes containing a {Fe(NO)₂} unit was determined from the results of a test set of complexes using a matrix of functionals and basis sets. Utilizing the optimum performer, the BP86 functional and a mixed SDD ECP basis set on iron and 6-311++G(d,p) on other atoms, a series of iron dinitrosyl complexes containing diverse ancillary ligands spanning the spectrochemical series was subsequently investigated. The electrochemical potentials of the pairs of "oxidized" and "reduced" DNIC complexes were evaluated for values occurring in the biological regime. Furthermore, as the {Fe(NO)₂} unit is capable of coordination in interesting yet dissimilar geometric motifs, bimetallic, tetrameric, and adamantane-like DNIC complexes have been investigated with our DFT methodology.

Computational chemists have successfully simulated many systems by applying the principles of quantum mechanics, while approximate molecular mechanical models have seen great utility in problems of biochemical interest. In recent years, a number of methods have been developed to combine the advantages of both techniques. In this study the so-called QM/MM method is developed and applied to the determination of the free energy of a simple Menshutkin S_N2 chemical reaction. This is an extremely demanding process, well beyond the computational capacity of an average workstation, and thus a Beowulf-class Linux cluster is constructed to perform the calculations, and tested for a variety of computational chemistry applications. A number of methods for improving the QM/MM approach are considered in this work. The Fluctuating Charge, or FlucQ, polarizable molecular mechanics force field is implemented in a flexible manner within the CHARMM package and tested for a variety of systems, including the S_N2 test case. Several drawbacks of the original method are addressed and overcome. Both molecular dynamics and Monte Carlo techniques are used within the QM/MM framework to investigate the S_N2 reaction, and the two methods are compared. Techniques are developed and tested to increase the efficiency of QM/MC calculations to the point where they become competitive with QM/MD. Extremely expensive QM treatments are shown to be required to obtain accurate energies for the Menshutkin reaction. A method is developed and tested, and compared with the traditional ONIOM technique, for dramatically reducing the computational time required to use these treatments for QM/MC simulations, paving the way for fully ab initio high basis set QM/MM simulation.

Interactions between single and double stranded oligonucleotides with SiO2 surfaces and the interactions between oligonucleotides and immobilized oligomers have been studied computationally. The oligonucleotide is the 18-base-pair sequence for the survival motor neuron gene SMN1. The oligomer consisted of a 50 unit 2-hydroxyethyl methacrylate (PHEMA) molecule. A linker used to tether the oligonucleotide was either a 10 Å or a 30 Å long succinimdyl 4-[N-maleimidomethyl]cyclohexane-1-caroxylate (sulfo-SMCC-Cn). The surface consisted of a SiO2 crystal that was 50 Å long and 50 Å wide, one unit thick and covered with modified-(3-aminopropyl)trimethoxysilane (m-APTMS) molecules. It was determined that explicit water, sodium counterions and excess salt were necessary to produce computationally stable oligonucleotide structures on surfaces. Artificial partial charges were introduced to the surface, and linkers, oligomers and oligonucleotides were immobilized and studied. The linkers collapsed onto a positive but not onto a negative surface. Oligomers moved closer to the SiO2 surface regardless of the surface charge. Immobilized oligonucleotides tilted significantly from an initial upright position but did not collapse completely onto the surfaces. The interactions between immobilized oligonucleotides and oligomers were examined. The number of oligomers surrounding the oligonucleotide was varied between two and four. Single stranded oligonucleotides were prevented from interacting with the surface as they were inhibited by the presence of oligomers. Double stranded oligonucleotides collapsed onto the surface when only two oligomers were present but remained upright when four oligomers were present. This was due to the four oligomers interacting with one another and effectively shielding the surface. The oligomers interacted with the bases in the single stranded oligonucleotides, making them energetically accessible. Presence of a high density of oligomers prevented the dsDNA from collapsing onto the surface. These results suggest design criteria for preparation of mixed oligonucleotide and oligomer films for use in biosensors.

Zugl.: Tübingen, Universität, Diss., 2006

Univ., Diss.--Erlangen-Nürnberg, 2000.

Stuttgart, Univ., Diss., 2000.

Techn. Universiẗat, Diss., 2003--Darmstadt.

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Biomolecule structural fluctuations determine function, regulating numerous biological processes My research has shed light on several interesting cases in which structural fluctuations have been identified to assess functional differences. Chapter 2 discusses the effects of structural rearrangement of the β2-β3 loop on the DNA binding affinity of the type 6 human papillomavirus E2 protein. Chapter 3 investigates the effects of phosphorylation on the C-terminal domain of Cdc37, a protein important in the Hsp90 chaperone cycle. Chapter 4 studies the effects on cyclycization on the conformational fluctuations of a γ-AApeptide used for high-throughput libraries. Chapter 5 is a structural study on a mini-fibril of spider dragline silk, in which a native-like ensemble was generated using temperature replica exchange. Chapter 6 investigates the structural features of repetitive motifs found in spider dragline silk when subject to both dope-like and fiber-like conditions. Chapter 7 elucidates conformational differences between the RXRα and the RXRβ ligand-binding domains and seeks to understand the atomic basis for different ligand binding affinities. This body of work has contributed to the understanding of conformational fluctuations and changes that occur in protein-DNA binding systems, drug-binding, regulation of chaperones via post-translations modifications and spider dragline silk.