Shen Congcong, Yin Jie, Wang Min, Yu Zhiping, Xu Xin, Zhou Zhongshun, Hu Yingshi, Xia Caijuan, Hu Guodong
Shandong Key Laboratory of Biophysics, Dezhou University, Dezhou, China.
Qingyun People's Hospital, Dezhou, China.
J Biomol Struct Dyn. 2024 Mar 26:1-14. doi: 10.1080/07391102.2024.2331627.
Mutations near allosteric sites can have a significant impact on the function of KRAS. Three specific mutations, K104Q, G12D/K104Q, and G12D/G75A, which are located near allosteric positions, were selected to investigate the molecular mechanisms behind mutation-induced influences on the activity of KRAS. Gaussian accelerated molecular dynamics (GaMD) simulations followed by the principal component analysis (PCA) were performed to improve the sampling of conformational states. The results revealed that these mutations significantly alter the structural flexibility, correlated motions, and dynamic behavior of the switch regions that are essential for KRAS binding to effectors or regulators. Furthermore, the mutations have a significant impact on the hydrogen bonding interactions between GDP and the switch regions, as well as on the electrostatic interactions of magnesium ions (Mg) with these regions. Our results verified that these mutations strongly influence the binding of KRAS to its effectors or regulators and allosterically regulate the activity. We believe that this work can provide valuable theoretical insights into a deeper understanding of KRAS function.
变构位点附近的突变可能对KRAS的功能产生重大影响。选择了位于变构位置附近的三个特定突变K104Q、G12D/K104Q和G12D/G75A，以研究突变诱导对KRAS活性影响背后的分子机制。进行了高斯加速分子动力学（GaMD）模拟，随后进行主成分分析（PCA），以改善构象状态的采样。结果表明，这些突变显著改变了开关区域的结构灵活性、相关运动和动态行为，而这些对于KRAS与效应器或调节剂的结合至关重要。此外，这些突变对GDP与开关区域之间的氢键相互作用以及镁离子（Mg）与这些区域的静电相互作用有重大影响。我们的结果证实，这些突变强烈影响KRAS与其效应器或调节剂的结合，并通过变构调节活性。我们相信这项工作可以为更深入理解KRAS功能提供有价值的理论见解。
