Gallardo Adan, Bogart Brandon M, Dutagaci Bercem
Department of Molecular and Cell Biology, University of California, Merced, 5200 North Lake Road, Merced, California 95343, United States.
J Chem Inf Model. 2022 Jun 27;62(12):3079-3089. doi: 10.1021/acs.jcim.2c00121. Epub 2022 Jun 10.
RNA polymerase II (Pol II) forms a complex with elongation factors to proceed to the elongation stage of the transcription process. In this work, we studied the elongation factor SPT5 and explored the protein-nucleic acid interactions for the isolated systems of KOW1 and KOW4 domains of SPT5 with DNA and RNA, respectively. We performed molecular dynamics (MD) simulations using three commonly used force fields that are CHARMM c36m, AMBER ff14sb, and ff19sb. Simulations showed strong protein-nucleic acid interactions and low electrostatic binding free energies for all force fields used. RNA was found to be highly dynamic with all force fields, while DNA had relatively more stable conformations with the AMBER force fields compared to that with CHARMM. Furthermore, we performed MD simulations of the complete elongation complex using CHARMM c36m and AMBER ff19sb force fields to compare the dynamics and interactions with the isolated systems. Similarly, strong KOW1 and DNA interactions were observed in the complete elongation complex simulations and DNA was further stabilized by a network of interactions involving SPT5-KOW1, SPT4, and rpb2 of Pol II. Overall, our study showed that the differences between CHARMM and AMBER force fields strongly affect the dynamics of the nucleic acids. CHARMM provides highly flexible DNA, while AMBER largely stabilizes the DNA structure. Although the presence of the entire interaction network stabilized the DNA and decreased the differences in the results from the two force fields, the discrepancies of the force fields for smaller systems may reflect their problems in generating accurate dynamics of nucleic acids.
RNA聚合酶II（Pol II）与延伸因子形成复合物，以进入转录过程的延伸阶段。在这项工作中，我们研究了延伸因子SPT5，并分别探索了SPT5的KOW1和KOW4结构域与DNA和RNA的分离系统中的蛋白质-核酸相互作用。我们使用三种常用的力场进行了分子动力学（MD）模拟，即CHARMM c36m、AMBER ff14sb和ff19sb。模拟结果表明，所有使用的力场都存在强烈的蛋白质-核酸相互作用和较低的静电结合自由能。发现RNA在所有力场中都具有高度动态性，而与CHARMM相比，DNA在AMBER力场中的构象相对更稳定。此外，我们使用CHARMM c36m和AMBER ff19sb力场对完整的延伸复合物进行了MD模拟，以比较其与分离系统的动力学和相互作用。同样，在完整的延伸复合物模拟中观察到了强烈的KOW1与DNA的相互作用，并且DNA通过涉及SPT5-KOW1、SPT4和Pol II的rpb2的相互作用网络进一步稳定。总体而言，我们的研究表明CHARMM和AMBER力场之间的差异强烈影响核酸的动力学。CHARMM提供了高度灵活的DNA，而AMBER在很大程度上稳定了DNA结构。尽管整个相互作用网络的存在稳定了DNA并减少了两个力场结果的差异，但较小系统中力场的差异可能反映了它们在生成准确的核酸动力学方面存在的问题。
