Chen Jianzhong, Zhang Shaolong, Zeng Qingkai, Wang Wei, Zhang Qinggang, Liu Xinguo
School of Science, Shandong Jiaotong University, Jinan, China.
School of Physics and Electronics, Shandong Normal University, Jinan, China.
Front Mol Biosci. 2022 May 2;9:912518. doi: 10.3389/fmolb.2022.912518. eCollection 2022.
Mutations of G12 in KRAS have been involved in different cancers. Multiple replica-Gaussian accelerated molecular dynamics (MR-GaMD) simulations are applied to investigate conformational changes of the switch domains caused by G12C, G12D and G12R. Free energy landscapes suggest that G12C, G12D and G12R induce more energetic states compared to the GTP-bound WT KRAS and make the conformations of the switch domains more disordered, which disturbs bindings of KRAS to effectors. Dynamics analyses based on MR-GaMD trajectory show that G12C, G12D and G12R not only change structural flexibility of the switch domains but also affect their motion behavior, indicating that these three mutations can be used to tune the activity of KRAS. The analyses of interaction networks verify that the instability in interactions of the GTP with the switch SⅠ plays an important role in the high disorder states of the switch domain. This work is expected to provide useful information for deeply understanding the function of KRAS.
KRAS基因中G12位点的突变与多种癌症相关。应用多重复制高斯加速分子动力学（MR-GaMD）模拟来研究由G12C、G12D和G12R引起的开关结构域的构象变化。自由能景观表明，与结合GTP的野生型KRAS相比，G12C、G12D和G12R诱导出更多的高能状态，并使开关结构域的构象更加无序，这干扰了KRAS与效应器的结合。基于MR-GaMD轨迹的动力学分析表明，G12C、G12D和G12R不仅改变了开关结构域的结构灵活性，还影响了它们的运动行为，表明这三种突变可用于调节KRAS的活性。相互作用网络分析证实，GTP与开关SⅠ相互作用的不稳定性在开关结构域的高无序状态中起重要作用。这项工作有望为深入理解KRAS的功能提供有用信息。
