This study focuses on investigating the effects of an oncogenic mutation (G12V) on the stability and interactions within the KRAS-RGL1 protein complex. The KRAS-RGL1 complex is of particular interest due to its relevance to KRAS-associated cancers and the potential for developing targeted drugs against the KRAS system. The stability of the complex and the allosteric effects of specific residues are examined to understand their roles as modulators of complex stability and function. Using molecular dynamics simulations, we calculate the mutual information, MI, between two neighboring residues at the interface of the KRAS-RGL1 complex, and employ the concept of interaction information, II, to measure the contribution of a third residue to the interaction between interface residue pairs. Negative II indicates synergy, where the presence of the third residue strengthens the interaction, while positive II suggests anti-cooperativity. Our findings reveal that MI serves as a dominant factor in determining the results, with the G12V mutation increasing the MI between interface residues, indicating enhanced correlations due to the formation of a more compact structure in the complex. Interestingly, although II plays a role in understanding three-body interactions and the impact of distant residues, it is not significant enough to outweigh the influence of MI in determining the overall stability of the complex. Nevertheless, II may nonetheless be a relevant factor to consider in future drug design efforts. This study provides valuable insights into the mechanisms of complex stability and function, highlighting the significance of three-body interactions and the impact of distant residues on the binding stability of the complex. Additionally, our findings demonstrate that constraining the fluctuations of a third residue consistently increases the stability of the G12V variant, making it challenging to weaken complex formation of the mutated species through allosteric manipulation. The novel perspective offered by this approach on protein dynamics, function, and allostery has potential implications for understanding and targeting other protein complexes involved in vital cellular processes. The results contribute to our understanding of the effects of oncogenic mutations on protein–protein interactions and provide a foundation for future therapeutic interventions in the context of KRAS-associated cancers and beyond.

中文翻译：

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变构中的协同作用和反协同作用：WT 和致癌 KRAS-RGL1 的分子动力学研究

本研究重点研究致癌突变 (G12V) 对 KRAS-RGL1 蛋白复合物稳定性和相互作用的影响。 KRAS-RGL1 复合物因其与 KRAS 相关癌症的相关性以及开发针对 KRAS 系统的靶向药物的潜力而受到特别关注。检查复合物的稳定性和特定残基的变构效应，以了解它们作为复合物稳定性和功能调节剂的作用。使用分子动力学模拟，我们计算了 KRAS-RGL1 复合物界面处两个相邻残基之间的相互信息 MI，并采用相互作用信息 II 的概念来测量第三个残基对界面之间相互作用的贡献残基对。负 II 表示协同作用，其中第三个残基的存在增强了相互作用，而正 II 表示反协同性。我们的研究结果表明，MI 是决定结果的主导因素，G12V 突变增加了界面残基之间的 MI，表明由于复合物中形成了更紧凑的结构，相关性增强。有趣的是，尽管 II 在理解三体相互作用和远处残基的影响方面发挥着重要作用，但在确定复合物的整体稳定性方面，它的重要性还不足以超过 MI 的影响。尽管如此，II 仍然可能是未来药物设计工作中需要考虑的相关因素。这项研究为复合物稳定性和功能的机制提供了有价值的见解，强调了三体相互作用的重要性以及远处残基对复合物结合稳定性的影响。此外，我们的研究结果表明，限制第三个残基的波动持续增加 G12V 变体的稳定性，使得通过变构操作削弱突变物种的复杂形成具有挑战性。这种方法提供的关于蛋白质动力学、功能和变构的新视角对于理解和靶向参与重要细胞过程的其他蛋白质复合物具有潜在的意义。这些结果有助于我们了解致癌突变对蛋白质-蛋白质相互作用的影响，并为未来 KRAS 相关癌症及其他癌症的治疗干预奠定基础。