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Title: Molecular Modeling of Damaged DNA Complexed with DNA Repair Proteins
Researcher: Kartheek Pitta
Guide(s): Marimuthu Krishnan
Keywords: Base Flipping
Computational Studies
DNA Bending
DNA Damage
DNA Repair
Physical Sciences,Multidisciplinary,Multidisciplinary Sciences
Umbrella Sampling
University: International Institute of Information Technology, Hyderabad
Completed Date: 31/07/2018
Abstract: DNA is the storehouse of genetic information in biological cells. It plays a vital role in transmission of the stored hereditary information from one generation to the next via the gene expression process. DNA damages caused by various damaging agents including free radicals,UV radiation, and anticancer drugs can alter genetic information and adversely affect gene expression pathways leading to various complex genetic disorders and cancers. To safeguard genetic information, biological cells have sophisticated survival mechanisms to recognize and rectify DNA damages with high fidelity. The task of recognition and repair of damaged DNA is carried out by a group of specific proteins. It is essential to understand the molecular basis of protein-mediated DNA damage repair to comprehend on the initiation and evolution of various complex genetic diseases and disorders. A critical molecular event that occurs during most protein-mediated DNA repair processes is the extrusion of orphaned bases at the damaged site facilitated by specific repairing enzymes. The molecular-level understanding of the mechanism, dynamics, and energetics of base extrusion is necessary to elucidate the molecular basis of protein-mediated DNA damage repair. The present thesis investigate the molecular mechanism and energetics of protein-induced base flipping and of DNA bending in various damaged DNA-protein complexes using molecular dynamics simulation and enhanced sampling free energy methods. In particular, we have explored thebmolecular mechanism of dinucleotide extrusion in a mismatched DNA (containing a stretch of three contiguous thymidine-thymidine base pairs) facilitated by Radiation sensitive 4 (RAD4), a key DNA repair protein, on an atom-by-atom basis using molecular dynamics (MD) and umbrella-sampling (US) simulations. Using atomistic models of RAD4-free and RAD4-bound mismatched DNA, the free energy profiles associated with extrusion of mismatched partner bases are determined for both systems.
Pagination: All Pages
Appears in Departments:Computational Natural Sciences

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chapter2.pdf123.82 kBAdobe PDFView/Open
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