了解功能活跃的JIP1片段的结构和Apo动力学,Journal of Chemical Information and Modeling

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了解功能活跃的JIP1片段的结构和Apo动力学
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2020-12-30 , DOI: 10.1021/acs.jcim.0c01008
Neda Ojaghlou ₁ , Justin Airas ₁ , Lauren M McRae ₁ , Cooper A Taylor ₁ , Bill R Miller ₂ , Carol A Parish ₁

Affiliation

最近的实验表明，C-Jun氨基末端激酶相互作用蛋白1（JIP1）结合并激活c-Jun N末端激酶（JNK）蛋白。JNK是细胞凋亡不可或缺的一部分，该过程的失调是诸如阿尔茨海默氏病（AD），肥胖症和癌症等疾病的致病因素。还已经表明，JIP1可以通过促进tau蛋白与JNK之间的相互作用来增加tau的磷酸化，这也可能是AD的致病因素。关于JIP1的结构和动力学知之甚少。然而，前350个残基的氨基酸组成表明它含有一个内在无序的区域。使用AMBER 14进行的分子动力学（MD）模拟用于研究功能活性JIP1 10mer片段的结构和动力学，以更好地了解该片段的溶解行为。对JIP1 10mer片段在10个不同种子中进行了2微秒的无偏MD，总共进行了20μs的仿真时间，然后通过经典聚类确定了10mer片段的七个结构稳定的构象。10mer合奏还用于构建马尔可夫状态模型（MSM），该模型确定了四个亚稳态，这些状态包含了通过经典尺寸缩减识别的七个构象族中的六个。基于此MSM，四个状态之间的构象互换通过两条主要途径发生，每种途径的概率通量分别为55％和44％。

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Understanding the Structure and Apo Dynamics of the Functionally Active JIP1 Fragment

Recent experiments indicate that the C-Jun amino-terminal kinase-interacting protein 1 (JIP1) binds to and activates the c-Jun N-terminal kinase (JNK) protein. JNK is an integral part of cell apoptosis, and misregulation of this process is a causative factor in diseases such as Alzheimer’s disease (AD), obesity, and cancer. It has also been shown that JIP1 may increase the phosphorylation of tau by facilitating the interaction between the tau protein and JNK, which could also be a causative factor in AD. Very little is known about the structure and dynamics of JIP1; however, the amino acid composition of the first 350 residues suggests that it contains an intrinsically disordered region. Molecular dynamics (MD) simulations using AMBER 14 were used to study the structure and dynamics of a functionally active JIP1 10mer fragment to better understand the solution behavior of the fragment. Two microseconds of unbiased MD was performed on the JIP1 10mer fragment in 10 different seeds for a total of 20 μs of simulation time, and from this, seven structurally stable conformations of the 10mer fragment were identified via classical clustering. The 10mer ensemble was also used to build a Markov state model (MSM) that identified four metastable states that encompassed six of the seven conformational families identified by classical dimensional reduction. Based on this MSM, conformational interconversions between the four states occur via two dominant pathways with probability fluxes of 55 and 44% for each individual pathway. Transitions between the initial and final states occur with mean first passage times of 31 (forward) and 16 (reverse) μs.

更新日期：2021-01-25

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