Department of Medicinal Chemistry, College of Pharmacy, University of Utah, 2000 East 30 South Skaggs 306, Salt Lake City, Utah 84112, United States.
Department of Medicinal Chemistry, Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, California 92010, United States.
J Chem Theory Comput. 2024 Nov 12;20(21):9354-9363. doi: 10.1021/acs.jctc.4c01164. Epub 2024 Oct 29.
Modified nucleic acids have surged as a popular therapeutic route, emphasizing the importance of nucleic acid research in drug discovery and development. Beyond well-known RNA vaccines, antisense oligonucleotides and aptamers can incorporate various modified nucleic acids to target specific biomolecules for various therapeutic activities. Molecular dynamics simulations can accelerate the design and development of these systems with noncanonical nucleic acids by observing intricate dynamic properties and relative stability on the all-atom level. However, modeling these modified systems is challenging due to the time and resources required to parametrize components outside default force field parameters. Here, we present modXNA, a tool to derive and build modified nucleotides for use with Amber force fields. Several nucleic acid systems varying in size and number of modification sites were used to evaluate the accuracy of modXNA parameters, and results indicate the dynamics and structure are preserved throughout the simulations. We detail the protocol for quantum mechanics charge derivation and describe a workflow for implementing modXNA in Amber molecular dynamics simulations, which includes updates and added features to CPPTRAJ.
修饰后的核酸已成为一种热门的治疗途径，凸显了核酸在药物发现和开发中的重要性。除了众所周知的 RNA 疫苗外，反义寡核苷酸和适体还可以整合各种修饰后的核酸，以针对特定的生物分子发挥各种治疗作用。分子动力学模拟可以通过观察全原子水平上复杂的动态特性和相对稳定性，加速这些具有非典型核酸的系统的设计和开发。然而，由于需要为默认力场参数之外的组件进行参数化，因此对这些修饰系统进行建模具有挑战性。在这里，我们介绍了 modXNA，这是一种用于衍生和构建 Amber 力场中使用的修饰核苷酸的工具。使用了几种大小和修饰位点数量不同的核酸系统来评估 modXNA 参数的准确性，结果表明整个模拟过程中动力学和结构得以保留。我们详细介绍了量子力学电荷推导的方案，并描述了在 Amber 分子动力学模拟中实现 modXNA 的工作流程，其中包括对 CPPTRAJ 的更新和添加功能。
