Department of Physics, North Carolina State University, Raleigh, NC 27695-8202, USA.
Nucleic Acids Res. 2018 Jan 25;46(2):942-955. doi: 10.1093/nar/gkx1186.
Atypical DNA secondary structures play an important role in expandable trinucleotide repeat (TR) and hexanucleotide repeat (HR) diseases. The cytosine mismatches in C-rich homoduplexes and hairpin stems are weakly bonded; experiments show that for certain sequences these may flip out of the helix core, forming an unusual structure termed an 'e-motif'. We have performed molecular dynamics simulations of C-rich TR and HR DNA homoduplexes in order to characterize the conformations, stability and dynamics of formation of the e-motif, where the mismatched cytosines symmetrically flip out in the minor groove, pointing their base moieties towards the 5'-direction in each strand. TRs have two non-equivalent reading frames, (GCC)n and (CCG)n; while HRs have three: (CCCGGC)n, (CGGCCC)n, (CCCCGG)n. We define three types of pseudo basepair steps related to the mismatches and show that the e-motif is only stable in (GCC)n and (CCCGGC)n homoduplexes due to the favorable stacking of pseudo GpC steps (whose nature depends on whether TRs or HRs are involved) and the formation of hydrogen bonds between the mismatched cytosine at position i and the cytosine (TRs) or guanine (HRs) at position i - 2 along the same strand. We also characterize the extended e-motif, where all mismatched cytosines are extruded, their extra-helical stacking additionally stabilizing the homoduplexes.
非典型 DNA 二级结构在可扩展三核苷酸重复（TR）和六核苷酸重复（HR）疾病中发挥着重要作用。富含胞嘧啶的同源双链体和发夹茎中的胞嘧啶错配结合较弱；实验表明，对于某些序列，这些碱基可能会从螺旋核心翻转出来，形成一种称为“e 基序”的异常结构。我们已经对富含胞嘧啶的 TR 和 HR DNA 同源双链体进行了分子动力学模拟，以研究 e 基序的构象、稳定性和形成动力学，其中错配的胞嘧啶在小沟中对称地翻转出来，指向每条链的 5'方向。TR 有两个不等效的阅读框，（GCC）n 和（CCG）n；而 HR 有三个：（CCCGGC）n、（CGGCCC）n、（CCCCGG）n。我们定义了三种与错配相关的伪碱基对步骤，并表明 e 基序仅在（GCC）n 和（CCCGGC）n 同源双链体中稳定，这是由于伪 GpC 步骤的有利堆积（其性质取决于涉及的是 TR 还是 HR）以及位置 i 处的错配胞嘧啶与同一链上位置 i-2 的胞嘧啶（TRs）或鸟嘌呤（HRs）之间形成氢键。我们还对扩展的 e 基序进行了表征，其中所有错配的胞嘧啶都被挤出，其额外的螺旋堆积进一步稳定了同源双链体。
