The Interplay between Structural Stability and Plasticity Determines Mutation Profiles and Chaperone Dependence in Protein Kinases,Journal of Chemical Theory and Computation

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The Interplay between Structural Stability and Plasticity Determines Mutation Profiles and Chaperone Dependence in Protein Kinases
Journal of Chemical Theory and Computation ( IF 5.7 ) Pub Date : 2018-01-10 00:00:00 , DOI: 10.1021/acs.jctc.7b00997
Antonella Paladino ₁ , Filippo Marchetti ₁ , Luca Ponzoni ₂ , Giorgio Colombo _{1,

3}

Affiliation

We present a novel comparative analysis of representative protein kinases to characterize the main dynamic and energetic determinants of functional regulation shared among different families. The relationships between stability and plasticity are also used to rationalize kinase tendencies to interact with the molecular chaperone Hsp90. These questions are tackled through newly developed molecular-dynamics-based methods of analysis of internal energy and dynamics applied to a total of 37 different systems, which represent wild-type and mutated proteins, including active and inactive states. Energetic decomposition analysis is coupled to multiple structural alignments and dynamic decomposition methods and identifies, across different families, common elements that underlie fold stabilization and conformational regulation. This analysis also exposes which substructures play a key role in determining chaperone dependence. Overall, the results highlight common interaction networks that underpin kinase stabilization, are modulated by mutations (even if located at a distance), and underlie their tendencies to act as clients or nonclients of Hsp90.

中文翻译：

结构稳定性和可塑性之间的相互作用决定了蛋白质激酶中的突变谱和伴侣依赖性。

我们提出了代表蛋白激酶的新型比较分析，以表征不同家族之间共享的功能调节的主要动态和能量决定因素。稳定性和可塑性之间的关系也用于合理化与分子伴侣Hsp90相互作用的激酶趋势。这些问题是通过新开发的基于分子动力学的内部能量和动力学分析方法解决的，这些方法应用于总共37个不同的系统，这些系统代表野生型和突变蛋白，包括活跃状态和非活跃状态。高能分解分析与多种结构比对和动态分解方法相结合，可识别不同家族中构成折叠稳定性和构象调控基础的常见元素。该分析还揭示了哪些亚结构在确定伴侣依赖性方面起着关键作用。总体而言，结果突出了支持激酶稳定的常见相互作用网络，这些相互作用网络受到突变的调节（即使位于相距较远的位置），并成为其充当Hsp90客户或非客户的趋势的基础。

更新日期：2018-01-10

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