Laboratory of Medicinal Chemistry, Rega Institute for Medical Research, Herestraat 49, Box 1030, B-3000 Leuven, Belgium.
Quantum Chemistry and Physical Chemistry, Celestijnenlaan 200f, Box 2404, B-3001, Leuven, Belgium.
Nucleic Acids Res. 2024 Apr 12;52(6):2836-2847. doi: 10.1093/nar/gkae135.
The field of synthetic nucleic acids with novel backbone structures [xenobiotic nucleic acids (XNAs)] has flourished due to the increased importance of XNA antisense oligonucleotides and aptamers in medicine, as well as the development of XNA processing enzymes and new XNA genetic materials. Molecular modeling on XNA structures can accelerate rational design in the field of XNAs as it contributes in understanding and predicting how changes in the sugar-phosphate backbone impact on the complementation properties of the nucleic acids. To support the development of novel XNA polymers, we present a first-in-class open-source program (Ducque) to build duplexes of nucleic acid analogs with customizable chemistry. A detailed procedure is described to extend the Ducque library with new user-defined XNA fragments using quantum mechanics (QM) and to generate QM-based force field parameters for molecular dynamics simulations within standard packages such as AMBER. The tool was used within a molecular modeling workflow to accurately reproduce a selection of experimental structures for nucleic acid duplexes with ribose-based as well as non-ribose-based nucleosides. Additionally, it was challenged to build duplexes of morpholino nucleic acids bound to complementary RNA sequences.
由于具有新型骨架结构的合成核酸 [异源核酸 (XNAs)] 的反义寡核苷酸和适体在医学中的重要性不断增加，以及 XNA 加工酶和新型 XNA 遗传材料的发展，该领域得到了蓬勃发展。对 XNA 结构进行分子建模可以加速 XNAs 领域的合理设计，因为它有助于理解和预测糖磷酸骨架的变化如何影响核酸的互补性质。为了支持新型 XNA 聚合物的开发，我们提出了一个一流的开源程序 (Ducque)，用于构建具有可定制化学性质的核酸类似物的双链体。详细介绍了如何使用量子力学 (QM) 为 Ducque 库扩展新的用户定义的 XNA 片段，并为基于标准包（如 AMBER）的分子动力学模拟生成基于 QM 的力场参数。该工具在分子建模工作流程中用于准确复制具有核糖核苷酸碱基和非核糖核苷酸碱基的核酸双链体的一系列实验结构。此外，它还被要求构建与互补 RNA 序列结合的吗啉代核酸的双链体。
