Institute of Biophysics of the Czech Academy of Sciences, Královopolská 135, 612 65 Brno, Czech Republic.
National Centre for Biomolecular Research, Faculty of Science, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic.
J Chem Inf Model. 2021 Nov 22;61(11):5644-5657. doi: 10.1021/acs.jcim.1c01047. Epub 2021 Nov 5.
The lone-pair···π (lp···π) (deoxy)ribose···nucleobase stacking is a recurring interaction in Z-DNA and RNAs that is characterized by sub-van der Waals lp···π contacts (<3.0 Å). It is a part of the structural signature of CpG Z-step motifs in Z-DNA and r(UNCG) tetraloops that are known to behave poorly in molecular dynamics (MD) simulations. Although the exact origin of the MD simulation issues remains unclear, a significant part of the problem might be due to an imbalanced description of nonbonded interactions, including the characteristic lp···π stacking. To gain insights into the links between lp···π stacking and MD, we present an in-depth comparison between accurate large-basis-set double-hybrid Kohn-Sham density functional theory calculations DSD-BLYP-D3/ma-def2-QZVPP (DHDF-D3) and data obtained with the nonbonded potential of the AMBER force field (AFF) for NpN Z-steps (N = G, A, C, and U). Among other differences, we found that the AFF overestimates the DHDF-D3 lp···π distances by ∼0.1-0.2 Å, while the deviation between the DHDF-D3 and AFF descriptions sharply increases in the short-range region of the interaction. Based on atom-in-molecule polarizabilities and symmetry-adapted perturbation theory analysis, we inferred that the DHDF-D3 versus AFF differences partly originate in identical nucleobase carbon atom Lennard-Jones (LJ) parameters despite the presence/absence of connected electron-withdrawing groups that lead to different effective volumes or vdW radii. Thus, to precisely model the very short CpG lp···π contact distances, we recommend revision of the nucleobase atom LJ parameters. Additionally, we suggest that the large discrepancy between DHDF-D3 and AFF short-range repulsive part of the interaction energy potential may significantly contribute to the poor performances of MD simulations of nucleic acid systems containing Z-steps. Understanding where, and if possible why, the point-charge-type effective potentials reach their limits is vital for developing next-generation FFs and for addressing specific issues in contemporary MD simulations.
孤立对···π（lp···π）（脱氧）核糖···碱基堆积是 Z-DNA 和 RNA 中常见的相互作用，其特征是亚范德华 lp···π 接触（<3.0 Å）。它是 Z-DNA 中 CpG Z 步基序和 r(UNCG)四链环结构特征的一部分，已知它们在分子动力学（MD）模拟中表现不佳。尽管 MD 模拟问题的确切原因仍不清楚，但问题的很大一部分可能是由于非键相互作用的描述不平衡，包括特征 lp···π 堆积。为了深入了解 lp···π 堆积与 MD 之间的联系，我们对准确的大基组双杂交 Kohn-Sham 密度泛函理论计算 DSD-BLYP-D3/ma-def2-QZVPP（DHDF-D3）与 AMBER 力场（AFF）获得的数据进行了深入比较，用于 NpN Z 步（N = G、A、C 和 U）。除其他差异外，我们发现 AFF 高估了 DHDF-D3 lp···π 距离约 0.1-0.2 Å，而 DHDF-D3 和 AFF 描述之间的偏差在相互作用的短程区域急剧增加。基于原子分子极化率和对称自适应微扰理论分析，我们推断 DHDF-D3 与 AFF 的差异部分源于相同的碱基碳原子伦纳德-琼斯（LJ）参数，尽管存在/不存在连接的吸电子基团，导致不同的有效体积或 vdW 半径。因此，为了精确模拟非常短的 CpG lp···π 接触距离，我们建议修订碱基原子 LJ 参数。此外，我们建议 DHDF-D3 和 AFF 相互作用能的短程排斥部分之间的巨大差异可能会严重影响包含 Z 步的核酸系统的 MD 模拟性能。了解有效点电荷型势能的极限在哪里，以及如果可能的话，为什么会达到极限，对于开发下一代力场和解决当代 MD 模拟中的具体问题至关重要。
