Histon kuyruğunda bulunan lizin amino asitlerinin demetilasyonuna yönelik kuantum mekanik (KK) ve melez kuantum mekanik/moleküler mekanik (MM) yöntemleri kullanarak reaksiyon mekanizması analizi

Chromatins, the basic structural units of the genetic material, consist of DNA and histone proteins. Eukaryotic DNA is wrapped around the histone proteins and they form `bead-like? structures. Histone proteins control many crucial cell regulatory processes, e.g. gene transcription, gene silencing, DNA replication and repair and etc., via post-translational modifications. Among the post-translational modifications, methylation was recently shown to be reversible by the discovery of Lysine-Specific Demethylase (LSD1) enzyme. As many previous studies have shown the relation of some cancer types and other diseases with the abnormalities in the balance of methylation/demethylation, drug molecule design based on the information gained from reaction mechanism studies becomes very crucial for the fight against these diseases.In this thesis, a chemically-reliable reaction mechanism is proposed for the demethylation of histone tail lysine residues and the reaction path analysis of this mechanism is carried out. Specifically, demethylation of H3 tail fourth lysine residue, i.e. H3K4, is analyzed. Potential and free energy profiles as well as structural properties are calculated using available Quantum Mechanical (QM), i.e. PM3, B3LYP and MP2, Molecular Mechanical (MM), i.e. UFF, as well as the hybrid QM/MM methods, i.e. ONIOM, which are implemented in Gaussian09 software package.As the result of the calculations, it is proved that the proposed chemical mechanism is actually simulating the real-life process and suitable for the demethylation of mono- and dimethylated lysines found on the histone tails. This comment is based on the calculated reaction rates, which are in high agreement with the experimental observations. Besides, some important observations made on the chemical mechanism, which enhances the understanding of how the demethylation process occurs at the molecular level, are explained and discussed in the thesis in fine details.These results offer an understanding for the details of the reaction mechanism, which will form a fundamental knowledge basis for further studies involving inhibitor molecules. By comparing the standard (i.e. in the absence of any inhibitor molecule) energy profiles and thermodynamic properties with the ones obtained in the presence of the inhibitor candidate, or directly comparing these profiles for different inhibitor candidates, one can have an understanding of the efficiency of the drug candidate for regulating the de/methylation balance. Knowing the key points in the reaction mechanism, one can design novel inhibitor molecules that are inspired by the reaction mechanism.