State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic and Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University , Shanghai 200240, China.
J Phys Chem B. 2015 Jan 15;119(2):474-81. doi: 10.1021/jp511359e. Epub 2014 Dec 31.
Phosphorothioation (PT), previously used in synthetic antisense drugs to arrest the transcription or translation process, is also a novel physiological modification in bacteria DNAs. In the previous study, we reported that Rp-phosphorothioation (Rp-PT) destabilizes B-type helix significantly, using a quantum-mechanics-based energy scoring function developed with a dinucleotide model ( Zhang et al. J. Phys. Chem. B , 2012 , 116 , 10639 - 10648 ). A consequent question surfaces in the field of the phosphorothioated DNA (S-DNA) research: does the endogenous chemical modification interact with the base sequence in the bacterial genomes, e.g., in terms of the most common structure of the B-type helix? In this work, we carried out further energetic analysis on the backbone relative energies calculated with the scoring function according to 16 groups of base-step classifications. Moreover, we conducted molecular dynamics simulations of the B-helical structure with the different base-pair steps, to investigate the detailed structural changes upon the O-/S-substitution. As a result, the Rp-PT modification definitively enhances the stiffness of the backbone and differentiates backbone stability as an interaction with base-steps. Furthermore, certain exceptional sequences such as GT and CC were highlighted in the structural analysis of the sulfur local contacts and relative orientation of double strands, indicating that Rp-PT can cross-talk with particular base-steps. The special effects between the phosphorothioation and base-step may be related to the conservative consensus observed highly frequently in bacterial genomes.
硫代磷酸化（PT），以前用于合成反义药物以阻止转录或翻译过程，也是细菌 DNA 中的一种新的生理修饰。在之前的研究中，我们报道了 Rp-硫代磷酸化（Rp-PT）显着破坏 B 型螺旋，使用基于双核苷酸模型开发的基于量子力学的能量评分函数（Zhang 等人，J. Phys. Chem. B，2012，116，10639-10648）。在硫代磷酸化 DNA（S-DNA）研究领域出现了一个问题：内源性化学修饰是否与细菌基因组中的碱基序列相互作用，例如在 B 型螺旋的最常见结构方面？在这项工作中，我们根据 16 组碱基步分类，对根据评分函数计算的骨架相对能进行了进一步的能量分析。此外，我们对不同碱基对步骤的 B-螺旋结构进行了分子动力学模拟，以研究 O-/S-取代时的详细结构变化。结果，Rp-PT 修饰明确增强了骨架的刚度，并区分了骨架稳定性作为与碱基步的相互作用。此外，在硫局部接触和双链相对取向的结构分析中突出了某些特殊序列，如 GT 和 CC，表明 Rp-PT 可以与特定的碱基步进行交叉对话。磷酸化与碱基步之间的特殊影响可能与细菌基因组中高度频繁观察到的保守共识有关。
