title: Molecular dynamics studies of trinucleotide repeat DNA involved in neurodegenerative disorders.
abstract: Expansion of trinucleotide repeat DNA of the classes CAG-CTG, CGG-CCG and GAA-TTC are found to be associated with several neurodegenerative disorders. Different mechanisms have been attributed to the expansion of triplets, mainly involving the formation of alternate secondary structures by such repeats. This paper reports the molecular dynamics simulation of triplet repeat DNA sequences to study the basic structural features of DNA that are responsible for the formation of structures such as hairpins and slip-strand DNA leading to expansion. All the triplet repeat sequences studied were found to be more flexible compared to the control sequence unassociated with disease. Moreover, flexibility was found to be in the order CAG-CTG > CGG-CCG approximately GAA-TTC, the highly flexible CAG-CTG repeat being the most common cause of neurodegenerative disorders. In another simulation, a single G-C to T-A mutation at the 9th position of the CAG-CTG repeat exhibited a reduction in bending compared to the pure 15-mer CAG-CTG repeat. EPM1 dodecamer repeat associated with the pathogenesis of progressive myoclonus epilepsy was also simulated and showed flexible nature suggesting a similar expansion mechanism.
authors.affiliation: Scientific and Engineering Computing Group, Centre for Development of Advanced Computing, Pune University Campus, Pune, Maharashtra 411007, India.
authors.forename: P V
authors.initials: PV
authors.lastname: Jithesh
authors.forename: P
authors.initials: P
authors.lastname: Singh
authors.forename: R
authors.initials: R
authors.lastname: Joshi
mesh_terms: D000465:Algorithms; D020137:Base Pair Mismatch; D003116:Color; D003198:Computer Simulation; D004247:DNA / Q000737:chemistry / Q000648:ultrastructure; D006801:Humans; D007477:Ions / Q000737:chemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000235:genetics*; D009690:Nucleic Acid Conformation; D009692:Nucleic Acid Heteroduplexes; D013816:Thermodynamics; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*; D014867:Water / Q000737:chemistry
chemical_list: D007477:Ions; D009692:Nucleic Acid Heteroduplexes; D014867:Water; D004247:DNA