Quantum Chemical Computational Study On Radical-Oxidized Mechanisms Of Methionine Model Peptide

Free radicals are a kind of molecules, ions or groups, which possess an unpaired electron.In the biological bodies, free radicals can be given birth to by a lot of pathways. It is foundfrom many researches that a great many diseases, such as degenerative nerve disease andageing, are related to free radicals. Amino acids are critical targets of various free radicals,due to their high abundance and low oxidation potential. As one of the most easily oxidableamino acids, the oxidation of Met not only represents an important posttranslationalmodification of proteins under conditions of oxidative stress, but also is linked to ageing andpathogenesis of Alzheimer's disease, prion disease and Parkinson's disease. Met's oxidationhas attracted considerable attention. Therefore, theoretical studies on radical-oxidizedmechanisms of Met model peptide are significant for understanding mechanisms ofpathology and filtrating drugs.To elucidate the amino acid oxidation mechanisms, various experimental techniques havebeen employed, in which pulse radiolysis may be the most powerful one, by which one canestablish an oxidation route map by assigning the transient spectra of various intermediates.However, the transient spectra assignment is a subject of frequent debate, because differentobservers may give distinct, even contradictory, assignments. At present, quantum chemicalcalculation, which has been employed widely in chemistry, life science and materialsciences, is one of the most important ways to investigate molecular structure-functionrelationship. Quantum chemical methods can calculate physicochemical properties of all thesmall molecules. Considering the successful use of density functional theory (DFT) ofquantum chemistry, especially time-dependent density functional theory (TD-DFT), inassisting the assignment of transient absorption spectra and the elucidation of redox reactionmechanisms for natural products, we have employed DFT to help elucidate oxidationmechanisms of Met model peptide in detail.In this dissertation, organic sulfides, i.e., dimethyl sulfide and 2, 2-dihydroxyethyl sulfide,are chosen to evaluate basis-set dependence and long-route solvent effect at first. ThenHOO·-H2O is employed to validate hydrogen-bond effect for molecular absorption spectra.At last, by means of evaluated DFT (especially TD-DFT) computational methods, wecalculate pulse radiolytic oxidation process of met model peptide, N-acetylmethionineamide in detail. It not only verified the previously proposed one-electron oxidationmechanisms of Met model peptide to large extent, but also proved the role of protonatedspecies played in one-electron oxidation of Met model peptide can not exclude. Thisprovided new clues to further experimental research. Moreover, oxidation mechanisms ofmethionine sulfoxide have been also calculated further.In summary, all of these evidences strongly suggest that DFT methods including TD-DFTare powerful tools to assist the elucidation of oxidation mechanisms of amino acids, andthus can serve as an important complement to experimental methodology in future studies.The dissertation consists of six chapters. In the first chapter, the current development ofthe radical-oxidized Met model peptide is introduced, including researching significance,existent questions, resolve approaches and so on. The theoretical and computational detailsof quantum chemistry are presented in the second chapter. Choices of theoretical parametersand corresponding computational methods are elucidated in Chapter three. Chapter four is toevaluate the computational methods of this dissertation. In Chapter five, the oxidativepathways of peptide model of Met, N-acetylmethionine amide, are calculated in detail, andwe consider roundly protonated species of model peptide of Met. In the last Chapter, themain contents are summarized, and a vista of the future on further research is made.