Binding modes of GDP, GTP and GNP to NRAS deciphered by using Gaussian accelerated molecular dynamics simulations.

IF 2.3 3区 环境科学与生态学 Q3 CHEMISTRY, MULTIDISCIPLINARY
H Y Bao, W Wang, H B Sun, J Z Chen
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引用次数: 5

Abstract

Probing binding modes of GDP, GTP and GNP to NRAS are of significance for understanding the regulation mechanism on the activity of RAS proteins. Four separate Gaussian accelerated molecular dynamics (GaMD) simulations were performed on the apo, GDP-, GTP- and GNP-bound NRAS. Dynamics analyses suggest that binding of three ligands highly affects conformational states of the switch domains from NRAS, which disturbs binding of NRAS to its effectors. The analyses of free energy landscapes (FELs) indicate that binding of GDP, GTP and GNP induces more energetic states of NRAS compared to the apo NRAS but the presence of GNP makes the switch domains more ordered than binding of GDP and GNP. The information of interaction networks of ligands with NRAS reveals that the π-π interaction of residue F28 and the salt bridge interactions of K16 and D119 with ligands stabilize binding of GDP, GTP and GNP to NRAS. Meanwhile magnesium ion plays a bridge role in interactions of ligands with NRAS, which is favourable for associations of GDP, GTP and GNP with NRAS. This work is expected to provide useful information for deeply understanding the function and activity of NRAS.

利用高斯加速分子动力学模拟,破解了GDP、GTP和GNP与NRAS的结合模式。
探讨GDP、GTP和GNP与NRAS的结合模式,对于了解RAS蛋白活性的调控机制具有重要意义。分别对载脂蛋白、GDP-、GTP-和gnp -结合的NRAS进行了四次高斯加速分子动力学(GaMD)模拟。动力学分析表明,三种配体的结合极大地影响了NRAS开关结构域的构象状态,从而干扰了NRAS与其效应体的结合。自由能景观(FELs)分析表明,与载脂蛋白NRAS相比,GDP、GTP和GNP的结合诱导了更多的NRAS能量状态,但GNP的存在使转换域比GDP和GNP的结合更有序。配体与NRAS相互作用网络的信息表明,残基F28的π-π相互作用以及K16和D119与配体的盐桥相互作用稳定了GDP、GTP和GNP与NRAS的结合。同时,镁离子在配体与NRAS的相互作用中起着桥梁作用,这有利于GDP、GTP和GNP与NRAS的关联。本研究有望为深入了解NRAS的功能和活性提供有用的信息。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
5.20
自引率
20.00%
发文量
78
审稿时长
>24 weeks
期刊介绍: SAR and QSAR in Environmental Research is an international journal welcoming papers on the fundamental and practical aspects of the structure-activity and structure-property relationships in the fields of environmental science, agrochemistry, toxicology, pharmacology and applied chemistry. A unique aspect of the journal is the focus on emerging techniques for the building of SAR and QSAR models in these widely varying fields. The scope of the journal includes, but is not limited to, the topics of topological and physicochemical descriptors, mathematical, statistical and graphical methods for data analysis, computer methods and programs, original applications and comparative studies. In addition to primary scientific papers, the journal contains reviews of books and software and news of conferences. Special issues on topics of current and widespread interest to the SAR and QSAR community will be published from time to time.
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