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基于分子动力学模拟研究YTHDF3与m6A修饰RNA的相互作用动力学及关键位点
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Abstract:
YTHDF3 (YTH domain family protein 3)能够特异性识别N6-甲基腺嘌呤(N6-methylladenosine, m6A)修饰的RNA，参与调控mRNA加工代谢、正常生理和异常病理等重要生命进程，与许多癌症息息相关。研究YTHDF3与m6A修饰RNA的相互作用动力学及关键位点具有重要意义。在本工作中，采用分子动力学(Molecular dynamics, MD)模拟方法研究了YTHDF3单体及与甲基化RNA复合物的动力学性质。研究发现，甲基化RNA的结合使得YTHDF3结构更加紧凑，构象更加稳定。运动相关性分析揭示了YTHDF3上负责结合甲基化RNA的重要区域。最后，构造运动相关性加权的复杂网络，识别了参与m6A修饰特异性识别的关键残基，与实验结果高度吻合。另外，还识别了一些远离结合界面但对结构稳定发挥重要功能的残基。本研究有助于理解YTHDF3与m6A修饰RNA之间的相互作用和关键位点，可为靶向药物设计提供重要信息。
YTHDF3 (YTH domain family protein 3) plays an important role in regulating mRNA processing, metabolism, normal physiology and abnormal pathology, which is associated with a variety of cancers. Investigating the interacting dynamics and key residues between YTHDF3 and m6A-mediated RNA is of important significance. Here, the molecular dynamics (MD) simulation is utilized to analyze the dynamic properties of YTHDF3 on apo and bound to methylated RNA states. The results reveal that upon RNA binding, the structure and the conformation of YTHDF3 become more com-pact and stable. The dynamical cross-correlated map analysis shows the important regions on YTHDF3 for the binding of methylated RNA. Finally, the covariance matrix is weighted to protein structure network for analyzing the key residues associated with specific interaction of m6A-modified RNA, which is consistent with the experimental information. In addition, we also find the residues which are far away from the binding interface but critical for the structural stability of YTHDF3. This study is helpful for the understanding of the interaction and key residues of YTHDF3 and m6A-mediated RNA, and can provide important information for the related drug design.
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