Jerzy Haber Institute of Catalysis and Surface Chemistry, Polish Academy of Sciences, ul. Niezapominajek 8, 30239 Cracow, Poland.
Department of Theoretical Chemistry, Institute of Chemical Sciences, Faculty of Chemistry, Maria Curie-Sklodowska University in Lublin pl. Maria Curie-Sklodowska 3, 20031 Lublin, Poland.
Molecules. 2022 Aug 1;27(15):4915. doi: 10.3390/molecules27154915.
Cytosine-rich DNA sequences are able to fold into noncanonical structures, in which semi-protonated cytosine pairs develop extra hydrogen bonds, and these bonds are responsible for the overall stability of a structure called the i-motif. The i-motif can be formed in many regions of the genome, but the most representative is the telomeric region in which the CCCTAA sequences are repeated thousands of times. The ability to reverse folding/unfolding in response to pH change makes the above sequence and i-motif very promising components of nanomachines, extended DNA structures, and drug carriers. Molecular dynamics analysis of such structures is highly beneficial due to direct insights into the microscopic structure of the considered systems. We show that Amber force fields for DNA predict the stability of the i-motif over a long timescale; however, these force fields are not able to predict folding of the cytosine-rich sequences into the i-motif. The reason is the kinetic partitioning of the folding process, which makes the transitions between various intermediates too time-consuming in atomistic force field representation. Application of coarse-grained force fields usually highly accelerates complex structural transitions. We, however, found that three of the most popular coarse-grained force fields for DNA (oxDNA, 3SPN, and Martini) were not able to predict the stability of the i-motif structure. Obviously, they were not able to accelerate the folding of unfolded states into an i-motif. This observation must be strongly highlighted, and the need to develop suitable extensions of coarse-grained force fields for DNA is pointed out. However, it will take a great deal of effort to successfully solve these problems.
富含胞嘧啶的 DNA 序列能够折叠成非canonical 结构，其中半质子化的胞嘧啶对形成额外的氢键，这些氢键负责整体稳定一种称为 i-motif 的结构。i-motif 可以在基因组的许多区域形成，但最具代表性的是端粒区域，其中 CCCTAA 序列重复数千次。能够响应 pH 值变化进行反向折叠/展开的能力使得上述序列和 i-motif 成为纳米机器、扩展 DNA 结构和药物载体的非常有前途的组成部分。对这些结构进行分子动力学分析非常有益，因为它可以直接深入了解所考虑系统的微观结构。我们表明，Amber 力场可在长时间尺度上预测 i-motif 的稳定性；然而，这些力场无法预测富含胞嘧啶的序列折叠成 i-motif。原因是折叠过程的动力学分配，使得在原子力场表示中各种中间体之间的转变过于耗时。粗粒化力场的应用通常可以高度加速复杂的结构转变。然而，我们发现三种最流行的 DNA 粗粒化力场（oxDNA、3SPN 和 Martini）都无法预测 i-motif 结构的稳定性。显然，它们无法加速展开状态折叠成 i-motif。必须强烈强调这一观察结果，并指出需要为 DNA 开发合适的粗粒化力场扩展。然而，成功解决这些问题需要付出巨大的努力。
