Exploring the RNA-Recognition Mechanism Using Supervised Molecular Dynamics (SuMD) Simulations: Toward a Rational Design for Ribonucleic-Targeting Molecules?
Exploring the RNA-Recognition Mechanism Using Supervised Molecular Dynamics (SuMD) Simulations: Toward a Rational Design for Ribonucleic-Targeting Molecules?
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DOI：
10.3389/fchem.2020.00107
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发表时间：
2020-02-27
影响因子：
5.5
通讯作者：
Moro, Stefano
中科院分区：
文献类型：
--
作者：
Bissaro, Maicol;Sturlese, Mattia;Moro, Stefano
尽管蛋白质代表了开发新药候选药物的分子靶点，但核糖核酸在药学上的重要性一直在逐渐增长。结构信息的日益可获得性揭示了特殊三维RNA排列的存在，与最初的预期相反，它可以通过小的化学实体或多肽来识别和选择性地调节。然而，由于这些大分子具有明显的构象灵活性、单电荷分布和溶剂分子的相关作用等特点，应用经典的计算方法(如分子对接)来合理开发RNA结合候选分子是复杂的。在这项工作中，我们因此验证并扩展了SuMD的适用范围，SuMD是一种全原子分子动力学协议，允许在纳秒时间尺度上加速分子识别事件的采样，以达到具有药物意义的核糖核苷酸目标。特别是，我们通过复制病毒或原核核糖核复合体的结合模式以及人工工程适配子的结合模式证明了方法的能力，准确度令人印象深刻。
Although proteins have represented the molecular target of choice in the development of new drug candidates, the pharmaceutical importance of ribonucleic acids has gradually been growing. The increasing availability of structural information has brought to light the existence of peculiar three-dimensional RNA arrangements, which can, contrary to initial expectations, be recognized and selectively modulated through small chemical entities or peptides. The application of classical computational methodologies, such as molecular docking, for the rational development of RNA-binding candidates is, however, complicated by the peculiarities characterizing these macromolecules, such as the marked conformational flexibility, the singular charges distribution, and the relevant role of solvent molecules. In this work, we have thus validated and extended the applicability domain of SuMD, an all-atoms molecular dynamics protocol that allows to accelerate the sampling of molecular recognition events on a nanosecond timescale, to ribonucleotide targets of pharmaceutical interest. In particular, we have proven the methodological ability by reproducing the binding mode of viral or prokaryotic ribonucleic complexes, as well as that of artificially engineered aptamers, with an impressive degree of accuracy.