Access to the three-dimensional structure of RNA enables an ability to gain a more profound understanding of its biological mechanisms, as well as the ability to design RNA-targeting drugs, which can take advantage of the unique chemical environment imposed by a folded RNA structure. Due to the dynamic and structurally complex properties of RNA, both experimental and traditional computational methods have difficulty in determining RNA’s 3D structure. Herein, we introduce TAPERSS (Theoretical Analyses, Prediction, and Evaluation of RNA Structures from Sequence), a physics-based fragment assembly method for predicting 3D RNA structures from sequence. Using a fragment library created using discrete path sampling calculations of RNA dinucleoside monophosphates, TAPERSS can sample the physics-based energy landscapes of any RNA sequence with relatively low computational complexity. We have benchmarked TAPERSS on 21 RNA tetraloops, using a combinatorial algorithm as a proof-of-concept. We show that TAPERSS was successfully able to predict the apo-state structures of all 21 RNA hairpins, with 16 of those structures also having low predicted energies as well. We demonstrate that TAPERSS performs most accurately on GNRA-like tetraloops with mostly stacked loop-nucleotides, while having limited success with more dynamic UNCG and CUYG tetraloops, most likely due to the influence of the RNA force field used to create the fragment library. Moreover, we show that TAPERSS can successfully predict the majority of the experimental non-apo states, highlighting its potential in anticipating biologically significant yet unobserved states. This holds great promise for future applications in drug design and related studies. With discussed improvements and implementation of more efficient sampling algorithms, we believe TAPERSS may serve as a useful tool for a physics-based conformational sampling of large RNA structures.

中文翻译：

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使用 RNA 二聚体的能量景观从序列预测 3D RNA 结构：在 RNA 四环中的应用


通过了解RNA的三维结构，能够更深入地了解其生物学机制，并能够设计RNA靶向药物，从而利用折叠RNA结构所施加的独特化学环境。由于RNA的动态和结构复杂特性，实验和传统计算方法都难以确定RNA的3D结构。在此，我们介绍TAPERSS（序列RNA结构的理论分析、预测和评估），这是一种基于物理的片段组装方法，用于根据序列预测3D RNA结构。使用通过 RNA 二核苷单磷酸离散路径采样计算创建的片段库，TAPERSS 可以以相对较低的计算复杂性对任何 RNA 序列的基于物理的能量景观进行采样。我们使用组合算法作为概念验证，在 21 个 RNA 四环上对 TAPRSS 进行了基准测试。我们表明，TAPERSS 能够成功预测所有 21 个 RNA 发夹的脱辅基态结构，其中 16 个结构的预测能量也较低。我们证明，TAPERSS 在大多数具有堆叠环核苷酸的类 GNRA 四环上执行最准确，而在更动态的 UNCG 和 CUYG 四环上的成功有限，很可能是由于用于创建片段库的 RNA 力场的影响。此外，我们还表明，TAPERSS 可以成功预测大多数实验性非 apo 状态，突显了其在预测具有生物学意义但未观察到的状态方面的潜力。这为药物设计和相关研究的未来应用带来了巨大的希望。 通过讨论改进和更有效采样算法的实现，我们相信 TAPESS 可以作为基于物理的大 RNA 结构构象采样的有用工具。