Jithesh P V, Singh P, Joshi R
Scientific and Engineering Computing Group, Centre for Development of Advanced Computing, Pune University Campus, Pune, Maharashtra 411007, India.
J Biomol Struct Dyn. 2001 Dec;19(3):479-95. doi: 10.1080/07391102.2001.10506756.
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.
已发现CAG-CTG、CGG-CCG和GAA-TTC类三核苷酸重复DNA的扩增与几种神经退行性疾病有关。三联体扩增的机制各不相同，主要涉及此类重复序列形成交替二级结构。本文报道了三核苷酸重复DNA序列的分子动力学模拟，以研究导致扩增的发夹和滑链DNA等结构形成所涉及的DNA基本结构特征。与未患疾病的对照序列相比，所有研究的三核苷酸重复序列都更具柔性。此外，发现柔性顺序为CAG-CTG > CGG-CCG≈GAA-TTC，高度柔性的CAG-CTG重复序列是神经退行性疾病最常见的病因。在另一项模拟中，与纯15聚体CAG-CTG重复序列相比，CAG-CTG重复序列第9位的单个G-C到T-A突变表现出弯曲度降低。还模拟了与进行性肌阵挛癫痫发病机制相关的EPM1十二聚体重复序列，其表现出柔性特征，提示类似的扩增机制。
