DNA trinucleotide repeats (TRs) can exhibit dynamic expansions by integer numbers of trinucleotides that lead to neurodegenerative disorders. Strand slipped hairpins during DNA replication, repair and/or recombination may contribute to TR expansion. Here, we combine single-molecule FRET experiments and molecular dynamics studies to elucidate slipping dynamics and conformations of (CAG)n TR hairpins. We directly resolve slipping by predominantly two CAG units. The slipping kinetics depends on the even/odd repeat parity. The populated states suggest greater stability for 5'-AGCA-3' tetraloops, compared with alternative 5'-CAG-3' triloops. To accommodate the tetraloop, even(odd)-numbered repeats have an even(odd) number of hanging bases in the hairpin stem. In particular, a paired-end tetraloop (no hanging TR) is stable in (CAG)n = even, but such situation cannot occur in (CAG)n = odd, where the hairpin is "frustrated'' and slips back and forth between states with one TR hanging at the 5' or 3' end. Trinucleotide interrupts in the repeating CAG pattern associated with altered disease phenotypes select for specific conformers with favorable loop sequences. Molecular dynamics provide atomic-level insight into the loop configurations. Reducing strand slipping in TR hairpins by sequence interruptions at the loop suggests disease-associated variations impact expansion mechanisms at the level of slipped hairpins.

中文翻译：

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CAG重复形成的DNA发夹中链滑动的动力学：序列奇偶校验和三核苷酸中断的作用。

DNA三核苷酸重复序列（TR）可以动态扩展整数，导致神经退行性疾病。在DNA复制，修复和/或重组过程中，发夹滑倒的发夹可能有助于TR的扩增。在这里，我们结合单分子FRET实验和分子动力学研究来阐明（CAG）n TR发夹的滑动动力学和构象。我们主要通过两个CAG单元直接解决滑移问题。滑移动力学取决于重复/奇偶校验。与替代的5'-CAG-3'三环相比，人口稠密的州对5'-AGCA-3'四环的稳定性更高。为了容纳四环，偶数（奇数）重复序列在发夹茎中具有偶数（奇数）悬挂碱基。特别是，与改变的疾病表型相关的重复CAG模式中的三核苷酸中断选择具有有利环序列的特定构象体。分子动力学提供了对环结构的原子级洞察力。通过在环上的序列中断减少TR发夹中的链滑动，表明与疾病相关的变异在发夹水平上影响了扩展机制。与改变的疾病表型相关的重复CAG模式中的三核苷酸中断选择具有有利环序列的特定构象体。分子动力学提供了对环结构的原子级洞察力。通过在环上的序列中断减少TR发夹中的链滑动，表明与疾病相关的变异在发夹水平上影响了扩展机制。