Program in Bioinformatics and Computational Biology, Graduate School, Chulalongkorn University, Bangkok, 10330, Thailand.
Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand.
Sci Rep. 2022 Jul 15;12(1):12137. doi: 10.1038/s41598-022-16252-w.
The Musashi (MSI) family of RNA-binding proteins, comprising the two homologs Musashi-1 (MSI1) and Musashi-2 (MSI2), typically regulates translation and is involved in cell proliferation and tumorigenesis. MSI proteins contain two ribonucleoprotein-like RNA-binding domains, RBD1 and RBD2, that bind single-stranded RNA motifs with a central UAG trinucleotide with high affinity and specificity. The finding that MSI also promotes the replication of Zika virus, a neurotropic Flavivirus, has triggered further investigations of the biochemical principles behind MSI-RNA interactions. However, a detailed molecular understanding of the specificity of MSI RBD1/2 interaction with RNA is still missing. Here, we performed computational studies of MSI1-RNA association complexes, investigating different RNA pentamer motifs using molecular dynamics simulations with binding free energy calculations based on the solvated interaction energy method. Simulations with Alphafold2 suggest that predicted MSI protein structures are highly similar to experimentally determined structures. The binding free energies show that two out of four RNA pentamers exhibit a considerably higher binding affinity to MSI1 RBD1 and RBD2, respectively. The obtained structural information on MSI1 RBD1 and RBD2 will be useful for a detailed functional and mechanistic understanding of this type of RNA-protein interactions.
MSI 家族的 RNA 结合蛋白，包括两个同源物 Musashi-1 (MSI1) 和 Musashi-2 (MSI2)，通常调节翻译，并参与细胞增殖和肿瘤发生。MSI 蛋白包含两个核糖核蛋白样 RNA 结合结构域，RBD1 和 RBD2，它们与具有中央 UAG 三核苷酸的单链 RNA 基序具有高亲和力和特异性。发现 MSI 还促进了神经嗜性 Flavivirus Zika 病毒的复制，这引发了对 MSI-RNA 相互作用背后的生化原理的进一步研究。然而，MSI RBD1/2 与 RNA 相互作用特异性的详细分子理解仍然缺失。在这里，我们使用基于溶剂化相互作用能方法的结合自由能计算进行分子动力学模拟，对 MSI1-RNA 结合复合物进行了计算研究，研究了不同的 RNA 五聚体基序。Alphafold2 的模拟表明，预测的 MSI 蛋白结构与实验确定的结构高度相似。结合自由能表明，四个 RNA 五聚体中的两个分别与 MSI1 RBD1 和 RBD2 具有相当高的结合亲和力。获得的关于 MSI1 RBD1 和 RBD2 的结构信息将有助于对这种 RNA-蛋白质相互作用进行详细的功能和机制理解。
