Molecular modelling studies of DNA damage recognition
Jiranusornkul, Supat (2008) Molecular modelling studies of DNA damage recognition. PhD thesis, University of Nottingham.
How DNA repair proteins search and recognise the rare sites of damage from the massive numbers of normal DNA remains poorly understood. FapydG (2,6-diamino-4-hydroxy-5-formamidopyrimidine) is one of the most prevalent guanine derived lesions involving opening of the imidazole ring. It is typically repaired by formamidopyrimidine-DNA glycosylase (Fpg) as an initial step in base excision repair; if not repaired, the lesion generates a G: C -+ T: A transversion. Unfortunately, studies on the recognition of FapydG have been hindered by difficulties to synthesise and incorporate the FapydG residue into a DNA duplex. Crystal structures of Fpg-DNA complexes have demonstrated three common recognition events: the protein specifically binding to the extrahelical lesion, bending DNA centred on the damaged base, and flipping the damage into the pocket. Thus, molecular modelling and dynamics simulation have been used to gather dynamical information of those recognition events for damaged and undamaged DNA. The simulations were initially performed when FapydG or G occurs in several dodecamer B-DNA sequences in aqueous solution, then inside the lesion-recognition pocket of Fpg, and during the flipping pathway from the helical stack to an extrahelical position.
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