无序肽与 Kelch 的结合：增强采样模拟的启示。
Binding of Disordered Peptides to Kelch: Insights from Enhanced Sampling Simulations.
机构信息
Department of Chemistry and Waterloo Institute for Nanotechnology, University of Waterloo , 200 University Avenue West, Waterloo, ON, Canada N2L 3G1.
Department of Biochemistry, University of Western Ontario , 1151 Richmond Street, London, ON, Canada N6A 3K7.
出版信息
J Chem Theory Comput. 2016 Jan 12;12(1):395-404. doi: 10.1021/acs.jctc.5b00868. Epub 2015 Dec 22.
Keap1 protein plays an essential role in regulating cellular oxidative stress response and is a crucial binding hub for multiple proteins, several of which are intrinsically disordered proteins (IDP). Among Kelch's IDP binding partners, NRF2 and PTMA are the two most interesting cases. They share a highly similar binding motif; however, NRF2 binds to Kelch with a binding affinity of approximately 100-fold higher than that of PTMA. In this study, we perform an exhaustive sampling composed of 6 μs well-tempered metadynamics and 2 μs unbiased molecular dynamics (MD) simulations aiming at characterizing the binding mechanisms and structural properties of these two peptides. Our results agree with previous experimental observations that PTMA is remarkably more disordered than NRF2 in both the free and bound states. This explains PTMA's lower binding affinity. Our extensive sampling also provides valuable insights into the vast conformational ensembles of both NRF2 and PTMA, supports the hypothesis of coupled folding-binding, and confirms the essential role of linear motifs in IDP binding.
Keap1 蛋白在调节细胞氧化应激反应中起着至关重要的作用，是多种蛋白质的关键结合中心，其中有几个是天然无序蛋白（IDP）。在 Kelch 的 IDP 结合伙伴中，NRF2 和 PTMA 是两个最有趣的例子。它们具有高度相似的结合基序；然而，NRF2 与 Kelch 的结合亲和力比 PTMA 高约 100 倍。在这项研究中，我们进行了全面的采样，包括 6 μs 良好调谐的元动力学和 2 μs 无偏分子动力学（MD）模拟，旨在表征这两种肽的结合机制和结构特性。我们的结果与先前的实验观察结果一致，即无论是在游离状态还是结合状态下，PTMA 都比 NRF2 显著更无序。这解释了 PTMA 较低的结合亲和力。我们广泛的采样还提供了有关 NRF2 和 PTMA 两者的巨大构象集合的有价值的见解，支持了折叠结合偶联的假设，并证实了线性基序在 IDP 结合中的重要作用。
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