Structural Characterization of Human Histone H4.1 by Tandem Nonlinear and Linear Ion Mobility Spectrometry Complemented with Molecular Dynamics Simulations.
Structural Characterization of Human Histone H4.1 by Tandem Nonlinear and Linear Ion Mobility Spectrometry Complemented with Molecular Dynamics Simulations.
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DOI：
10.1021/acsomega.1c03744
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发表时间：
2021-11-09
期刊：
影响因子：
4.1
通讯作者：
Fernandez-Lima F
中科院分区：
文献类型：
--
作者：
Pham KN;Fernandez-Lima F
细胞外组蛋白H4由于其在脓毒症和其他疾病的器官衰竭中的作用而成为一个有吸引力的药物靶点。为了使用计算机方法识别抑制剂，需要组蛋白H4结构动力学和三维（3D）结构坐标的信息。在这里，无DNA组蛋白H4 1型（H4.1）的特点是利用串联非线性和线性离子迁移谱（FAIMS-TIMS）耦合质谱（MS）补充分子动力学（MD）模拟。H4.1的气相结构取决于起始溶液条件，这由电荷态分布、迁移率分布和碰撞诱导展开（CIU）途径的差异来证明。实验结果表明，H4.1具有从紧凑（C）到部分折叠（P）和随后的伸长（E）结构的多种构象类型。分子动力学模拟提供了候选的组蛋白H4.1单体在溶液中的结构和使用FAIMS-IMS-TOF MS作为电荷状态和迁移率分布的函数观察到的气相结构。FAIMS-TIMS实验结果与理论偶极计算相结合揭示了电荷分布在高电场下H4.1细长结构偶极排列中的重要作用。基于实验IMS-MS和MD结果，对无DNA的H2A.1和H4.1的二级和一级结构进行了比较。
Extracellular histone H4 is an attractive drug target owing to its roles in organ failure in sepsis and other diseases. To identify inhibitors using in silico methods, information on histone H4 structural dynamics and three-dimensional (3D) structural coordinates is required. Here, DNA-free histone H4 type 1 (H4.1) was characterized by utilizing tandem nonlinear and linear ion mobility spectrometry (FAIMS-TIMS) coupled to mass spectrometry (MS) complemented with molecular dynamics (MD) simulations. The gas-phase structures of H4.1 are dependent on the starting solution conditions, evidenced by differences in charge state distributions, mobility distributions, and collision-induced unfolding (CIU) pathways. The experimental results show that H4.1 adopts diverse conformational types from compact (C) to partially folded (P) and subsequently elongated (E) structures. Molecular dynamics simulations provided candidate structures for the histone H4.1 monomer in solution and for the gas-phase structures observed using FAIMS-IMS-TOF MS as a function of the charge state and mobility distribution. A combination of the FAIMS-TIMS experimental results with theoretical dipole calculations reveals the important role of charge distribution in the dipole alignment of H4.1 elongated structures at high electric fields. A comparison of the secondary and primary structures of DNA-free H2A.1 and H4.1 is made based on the experimental IMS-MS and MD findings.
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影响因子：
7.4
作者：
Jeanne Dit Fouque K;Garabedian A;Leng F;Tse-Dinh YC;Ridgeway ME;Park MA;Fernandez-Lima F
通讯作者：
Fernandez-Lima F
DOI：
10.1016/j.bbagrm.2011.09.007
发表时间：
2012-03
影响因子：
4.7
作者：
Keck, Kristin M.;Pemberton, Lucy F.
通讯作者：
Pemberton, Lucy F.
影响因子：
3.3
作者：
Koeniger, SL;Merenbloom, SI;Clemmer, DE
通讯作者：
Clemmer, DE
影响因子：
3.3
作者：
Fouque, Kevin Jeanne Dit;Moreno, Javier;Fernandez-Lima, Francisco
通讯作者：
Fernandez-Lima, Francisco
影响因子：
8
作者：
Khoa Pham;Dhulipala, Gangadhar;Miksovska, Jaroslava
通讯作者：
Miksovska, Jaroslava