Modeling pK Shift in DNA Triplexes Containing Locked Nucleic Acids,Journal of Chemical Information and Modeling

当前位置： X-MOL 学术 › J. Chem. Inf. Model. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Modeling pK Shift in DNA Triplexes Containing Locked Nucleic Acids
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2018-03-14 00:00:00 , DOI: 10.1021/acs.jcim.7b00741
Yossa Dwi Hartono _{1,

2} , You Xu ₁ , Andrey Karshikoff ₁ , Lennart Nilsson ₁ , Alessandra Villa ₁

Affiliation

The protonation states for nucleic acid bases are difficult to assess experimentally. In the context of DNA triplex, the protonation state of cytidine in the third strand is particularly important, because it needs to be protonated in order to form Hoogsteen hydrogen bonds. A sugar modification, locked nucleic acid (LNA), is widely used in triplex forming oligonucleotides to target sites in the human genome. In this study, the parameters for LNA are developed in line with the CHARMM nucleic acid force field and validated toward the available structural experimental data. In conjunction, two computational methods were used to calculate the protonation state of the third strand cytidine in various DNA triplex environments: λ-dynamics and multiple pH regime. Both approaches predict pK of this cytidine shifted above physiological pH when cytidine is in the third strand in a triplex environment. Both methods show an upshift due to cytidine methylation, and a small downshift when the sugar configuration is locked. The predicted pK values for cytidine in DNA triplex environment can inform the design of better-binding oligonucleotides.

中文翻译：

在包含锁定核酸的DNA三链体中模拟p K位移

核酸碱基的质子化状态难以通过实验评估。在DNA三链体的情况下，在第三链中胞苷的质子化状态特别重要，因为它需要被质子化以形成Hoogsteen氢键。糖修饰的锁核酸（LNA）被广泛用于形成三链体的寡核苷酸中，以靶向人类基因组中的位点。在这项研究中，根据CHARMM核酸力场开发了LNA的参数，并针对可用的结构实验数据进行了验证。结合使用两种计算方法来计算各种DNA三链体环境中第三链胞苷的质子化状态：λ动力学和多种pH方案。两种方法都预测p K当胞苷在三链体环境中处于第三链中时，该胞苷的一半转移到高于生理pH。两种方法均由于胞苷甲基化而显示出升档，而当糖构型被锁定时则显示出小的降档。DNA三链体环境中胞苷的预测p K值可为结合性更好的寡核苷酸设计提供参考。

更新日期：2018-03-14

点击分享查看原文

点击收藏

公开下载

阅读更多本刊最新论文本刊介绍/投稿指南11