Conformations of KRAS4B Affected by Its Partner Binding and G12C Mutation: Insights from GaMD Trajectory-Image Transformation-Based Deep Learning,Journal of Chemical Information and Modeling

当前位置： X-MOL 学术 › J. Chem. Inf. Model. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Conformations of KRAS4B Affected by Its Partner Binding and G12C Mutation: Insights from GaMD Trajectory-Image Transformation-Based Deep Learning
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2024-08-28 , DOI: 10.1021/acs.jcim.4c01174
Jianzhong Chen _{1,

2} , Jian Wang ₁ , Wanchun Yang ₁ , Lu Zhao ₁ , Guodong Hu ₂

Affiliation

Binding of partners and mutations highly affects the conformational dynamics of KRAS4B, which is of significance for deeply understanding its function. Gaussian accelerated molecular dynamics (GaMD) simulations followed by deep learning (DL) and principal component analysis (PCA) were carried out to probe the effect of G12C and binding of three partners NF1, RAF1, and SOS1 on the conformation alterations of KRAS4B. DL reveals that G12C and binding of partners result in alterations in the contacts of key structure domains, such as the switch domains SW1 and SW2 together with the loops L4, L5, and P-loop. Binding of NF1, RAF1, and SOS1 constrains the structural fluctuation of SW1, SW2, L4, and L5; on the contrary, G12C leads to the instability of these four structure domains. The analyses of free energy landscapes (FELs) and PCA also show that binding of partners maintains the stability of the conformational states of KRAS4B while G12C induces greater mobility of the switch domains SW1 and SW2, which produces significant impacts on the interactions of GTP with SW1, L4, and L5. Our findings suggest that partner binding and G12C play important roles in the activity and allosteric regulation of KRAS4B, which may theoretically aid in further understanding the function of KRAS4B.

中文翻译：

KRAS4B 的构象受其伴侣结合和 G12C 突变的影响：来自 GaMD 轨迹-基于图像变换的深度学习的见解

伴侣和突变的结合高度影响KRAS4B的构象动力学，这对于深入理解其功能具有重要意义。通过高斯加速分子动力学 (GaMD) 模拟，然后进行深度学习 (DL) 和主成分分析 (PCA)，以探讨 G12C 以及三个伙伴 NF1、RAF1 和 SOS1 的结合对 KRAS4B 构象改变的影响。 DL 揭示 G12C 和伴侣的结合导致关键结构域的接触发生改变，例如开关域 SW1 和 SW2 以及环 L4、L5 和 P 环。 NF1、RAF1和SOS1的结合限制了SW1、SW2、L4和L5的结构波动；相反，G12C导致这四个结构域的不稳定。自由能景观 (FEL) 和 PCA 的分析还表明，伴侣的结合维持了 KRAS4B 构象状态的稳定性，而 G12C 诱导开关结构域 SW1 和 SW2 更大的移动性，这对 GTP 与 SW1 的相互作用产生重大影响、L4 和 L5。我们的研究结果表明，伴侣结合和 G12C 在 KRAS4B 的活性和变构调节中发挥重要作用，这在理论上可能有助于进一步了解 KRAS4B 的功能。

更新日期：2024-08-29

点击分享查看原文

点击收藏

阅读更多本刊新发论文本刊介绍/投稿指南