Rieger Manuel, Zacharias Martin
Physics Department and Center of Protein Assemblies, Technical University of Munich, 85748 Garching, Germany.
J Phys Chem B. 2022 May 26;126(20):3640-3647. doi: 10.1021/acs.jpcb.2c01138. Epub 2022 May 12.
The thermodynamic stability of double-stranded (ds)DNA depends on its sequence. It is influenced by the base pairing and stacking with neighboring bases along DNA molecules. Semiempirical schemes are available that allow us to predict the thermodynamic stability of DNA sequences based on empirically derived nearest-neighbor contributions of base pairs formed in the context of all possible nearest-neighbor base pairs. Current molecular dynamics (MD) simulations allow one to simulate the dynamics of DNA molecules in good agreement with experimentally obtained structures and available data on conformational flexibility. However, the suitability of current force field methods to reproduce dsDNA stability and its sequence dependence has been much less well tested. We have employed alchemical free-energy simulations of whole base pair transversions in dsDNA and in unbound single-stranded partner molecules. Such transversions change the sequence context but not the nucleotide content or base pairing in dsDNA and allow a direct comparison with the empirical nearest-neighbor dsDNA stability model. For the alchemical free-energy changes in the unbound single-stranded (ss)DNA partner molecules, we tested different setups assuming either complete unstacking or unrestrained simulations with partial stacking in the unbound ssDNA. The free-energy simulations predicted nearest-neighbor effects of similar magnitude, as observed experimentally but showed overall limited correlation with experimental data. An inaccurate description of stacking interactions and other possible reasons such as the neglect of electronic polarization effects are discussed. The results indicate the need to improve the realistic description of stacking interactions in current molecular mechanic force fields.
双链（ds）DNA的热力学稳定性取决于其序列。它受到沿DNA分子与相邻碱基的碱基配对和堆积的影响。现有半经验方案，可让我们根据在所有可能的近邻碱基对背景下形成的碱基对的经验性近邻贡献来预测DNA序列的热力学稳定性。当前的分子动力学（MD）模拟能够模拟DNA分子的动力学，与实验获得的结构以及构象灵活性的现有数据高度吻合。然而，当前的力场方法在再现dsDNA稳定性及其序列依赖性方面的适用性尚未得到充分测试。我们采用了对dsDNA和未结合的单链配对分子中整个碱基对颠换的炼金术自由能模拟。这种颠换改变了序列背景，但不改变dsDNA中的核苷酸含量或碱基配对，并允许与经验性近邻dsDNA稳定性模型进行直接比较。对于未结合的单链（ss）DNA配对分子中的炼金术自由能变化，我们测试了不同的设置，假设要么完全解堆积，要么对未结合的ssDNA进行部分堆积的无约束模拟。自由能模拟预测了与实验观察到的相似大小的近邻效应，但总体上与实验数据的相关性有限。讨论了堆积相互作用的不准确描述以及其他可能的原因，如对电子极化效应的忽视。结果表明需要改进当前分子力学力场中堆积相互作用的真实描述。
