National Centre for Biomolecular Research, Faculty of Science, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic.
CEITEC─Central European Institute of Technology, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic.
J Chem Inf Model. 2021 Dec 27;61(12):6000-6011. doi: 10.1021/acs.jcim.1c00731. Epub 2021 Nov 15.
Mismatched base pairs alter the flexibility and intrinsic curvature of DNA. The role of such DNA features is not fully understood in the mismatch repair pathway. MutS/DNA complexes exhibit DNA bending, PHE intercalation, and changes of base-pair parameters near the mismatch. Recently, we have shown that base-pair opening in the absence of MutS can discriminate mismatches from canonical base pairs better than DNA bending. However, DNA bending in the absence of MutS was found to be rather challenging to describe correctly. Here, we present a computational study on the DNA bending of canonical and G/T mismatched DNAs. Five types of geometric parameters covering template-based bending toward the experimental DNA structure, global, and local geometry parameters were employed in biased molecular dynamics in the absence of MutS. None of these parameters showed higher discrimination than the base-pair opening. Only roll could induce a sharply localized bending of DNA as observed in the experimental MutS/DNA structure. Further, we demonstrated that the intercalation of benzene mimicking PHE decreases the energetic cost of DNA bending without any effect on mismatch discrimination.
错配碱基对改变了 DNA 的柔韧性和固有曲率。在错配修复途径中，这种 DNA 特征的作用尚未完全了解。MutS/DNA 复合物表现出 DNA 弯曲、PHE 嵌入以及错配附近碱基对参数的变化。最近，我们已经表明，在没有 MutS 的情况下，碱基对的打开可以比 DNA 弯曲更好地区分错配与标准碱基对。然而，发现没有 MutS 的 DNA 弯曲很难正确描述。在这里，我们对标准和 G/T 错配 DNA 的 DNA 弯曲进行了计算研究。在没有 MutS 的情况下，我们在偏置分子动力学中使用了五种涵盖模板基弯曲朝向实验 DNA 结构的几何参数、全局和局部几何参数。这些参数都没有比碱基对打开具有更高的区分度。只有滚转角可以诱导 DNA 产生类似于实验 MutS/DNA 结构中观察到的局部弯曲。此外，我们证明了苯模拟 PHE 的嵌入可以降低 DNA 弯曲的能量成本，而对错配的区分没有任何影响。
