Molecular Dynamics Investigation into the Stability of KRas and CRaf Multimeric Complexes.

IF 2.8 2区化学 Q3 CHEMISTRY, PHYSICAL

The Journal of Physical Chemistry B Pub Date : 2025-04-03 Epub Date: 2025-03-24 DOI:10.1021/acs.jpcb.4c08767

Chongli Geng, Juan Zeng, Xianming Deng, Fei Xia, Xin Xu

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引用次数: 0

Abstract

In the Ras/Raf/MAPK signaling pathway, Ras and Raf proteins interact synergistically to form a tetrameric complex. NMR experiments have demonstrated that Ras dimerizes in solution and binds stably to Raf, forming Ras·Raf complexes. In this study, we constructed the ternary and quaternary complexes of KRas and CRaf based on crystal structures, denoted as (KRas)₂·CRaf and (KRas)₂·(CRaf)₂, respectively. Molecular dynamics (MD) simulations were performed to investigate the stability of these complexes, while hydrogen bonds as well as salt bridges formed at the protein-protein interaction interfaces were analyzed based on simulation trajectories. The results revealed that the KRas·CRaf complex is more stable in explicit solvent compared with the KRas dimer. Formation of the stable quaternary complex (KRas)₂·(CRaf)₂ might be attributed to the association of two binary KRas·CRaf complexes. Additionally, MD simulations of the KRasG12D·CRaf complex revealed a stable and extended binding site at the KRas-CRaf interaction interface. This binding site was identified as a potential therapeutic target to block abnormal signal transmission in the pathway.

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KRas和CRaf多聚物稳定性的分子动力学研究。

在Ras/Raf/MAPK信号通路中，Ras和Raf蛋白协同作用形成四聚体复合物。核磁共振实验表明，Ras在溶液中二聚并与Raf稳定结合，形成Ras·Raf配合物。在本研究中，我们基于晶体结构构建了KRas和CRaf的三元和四元配合物，分别记为（KRas）2·CRaf和（KRas）2·（CRaf）2。通过分子动力学（MD）模拟研究了这些配合物的稳定性，并基于模拟轨迹分析了在蛋白质-蛋白质相互作用界面上形成的氢键和盐桥。结果表明，KRas·CRaf配合物在外显溶剂中比KRas二聚体更稳定。稳定的四元配合物（KRas）2·（CRaf）2的形成可能归因于两个二元KRas·CRaf配合物的结合。此外，KRasG12D·CRaf复合物的MD模拟显示，KRasG12D·CRaf复合物在KRas-CRaf相互作用界面上有一个稳定且扩展的结合位点。该结合位点被认为是阻断该通路异常信号传递的潜在治疗靶点。

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来源期刊

The Journal of Physical Chemistry B 化学-物理化学

CiteScore

5.80

自引率

9.10%

发文量

965

审稿时长

1.6 months

期刊介绍： An essential criterion for acceptance of research articles in the journal is that they provide new physical insight. Please refer to the New Physical Insights virtual issue on what constitutes new physical insight. Manuscripts that are essentially reporting data or applications of data are, in general, not suitable for publication in JPC B.