现在很清楚,RNA分子可以在几种生物过程中发挥积极作用。因此,越来越多的RNA逐渐被鉴定为潜在的药物靶标.特别是,非编码RNA可以采用适合药物结合的高度组织化构象。然而,由于其复杂的结构动力学和高电荷密度,RNA仍然被认为是具有挑战性的靶标。因此,阐明药物-RNA结合的相关特征是推进药物发现的基础。这里,通过使用分子动力学模拟,我们将配体与蛋白质结合的关键特征与RNA中观察到的特征进行了比较。具体来说,我们在(I)靶标的构象灵活性方面探索异同,(ii)静电对结合自由能的贡献,和(iii)水和配体动力学。作为一个测试用例,我们检查相同配体的结合,即核黄素,蛋白质和RNA靶标,特别是核黄素(RF)激酶和黄素单核苷酸(FMN)核糖开关。FMN核糖开关表现出增强的波动,并探索了更宽的构象空间,与蛋白质靶标相比,强调了RNA灵活性在配体结合中的重要性。相反,发现了对核黄素结合自由能的类似静电贡献。最后,与RF激酶相比,FMN核糖开关中水分子的稳定性更高,可能是由于不同的形状和极性的口袋。
It is nowadays clear that RNA molecules can play active roles in several biological processes. As a result, an increasing number of RNAs are gradually being identified as potentially druggable targets. In particular, noncoding RNAs can adopt highly organized conformations that are suitable for drug binding. However, RNAs are still considered challenging targets due to their complex structural dynamics and high charge density. Thus, elucidating relevant features of drug-RNA binding is fundamental for advancing drug discovery. Here, by using Molecular Dynamics simulations, we compare key features of ligand binding to proteins with those observed in RNA. Specifically, we explore similarities and differences in terms of (i) conformational flexibility of the target, (ii) electrostatic contribution to binding free energy, and (iii) water and ligand dynamics. As a test
case, we examine binding of the same ligand, namely riboflavin, to protein and RNA targets, specifically the riboflavin (RF) kinase and flavin mononucleotide (FMN) riboswitch. The FMN riboswitch exhibited enhanced fluctuations and explored a wider conformational space, compared to the protein target, underscoring the importance of RNA flexibility in ligand binding. Conversely, a similar electrostatic contribution to the binding free energy of riboflavin was found. Finally, greater stability of water molecules was observed in the FMN riboswitch compared to the RF kinase, possibly due to the different shape and polarity of the pockets.