Multiscale computational study of ligand binding pathways: Case of p38 MAP kinase and its inhibitors
Multiscale computational study of ligand binding pathways: Case of p38 MAP kinase and its inhibitors
复制标题
DOI：
10.1016/j.bpj.2021.08.026
复制
发表时间：
2021-09-21
影响因子：
3.4
通讯作者：
Huang, Yu-Ming M.
中科院分区：
文献类型：
--
作者：
Huang, Yu-Ming M.
蛋白激酶是近10年来最重要的药物靶点之一。了解抑制剂缔合过程将深刻影响具有优选结合动力学的新结合剂设计。然而，经过十多年的努力，仍然缺乏一个完整的原子水平的激酶抑制剂结合途径的研究。由于所有的激酶都有一个相似的骨架，我们使用p38激酶作为模型系统来研究抑制剂结合激酶的构象动力学和自由能转换。在这项工作中，两个主要的激酶构象，Asp-Phe-Gly（DFG）-在和DFG-out，和三种类型的抑制剂，类型I，II和III，进行了彻底的研究。我们进行了布朗动力学模拟和高达340 us的高斯加速分子动力学模拟，以捕获抑制剂结合路径和一系列的构象转变的p38激酶从其载脂蛋白到受体结合的形式。本文报道了18种成功的结合轨迹，包括所有类型的抑制剂。我们的模拟表明抑制剂的招聘机制，一个更快的配体缔合步骤预先存在的DFG-in/DFG-out p38蛋白，随后是一个较慢的分子重排步骤，以调整蛋白质-配体构象，然后在能量景观的转变，以达到最终的结合状态。配体缔合过程也反映了I型和II型/111抑制剂分别通过ATP和变构通道结合的能量优势。这些不同的结合途径直接导致不同类型的p38抑制剂的快速（I型结合剂）和缓慢（II/III型结合剂）动力学。我们的研究结果也呼应了最近的研究p38抑制剂解离，这意味着配体解结合可能会经历一个相反的结合路径，这两个过程共享类似的metastates。这项研究加深了对激酶结合过程的分子和能量特征的理解，并将从动力学角度启发未来的药物开发。
Protein kinases are one of the most important drug targets in the past 10 years. Understanding the inhibitor association processes will profoundly impact new binder designs with preferred binding kinetics. However, after more than a decade of effort, a complete atomistic-level study of kinase inhibitor binding pathways is still lacking. As all kinases share a similar scaffold, we used p38 kinase as a model system to investigate the conformational dynamics and free energy transition of inhibitor binding toward kinases. Two major kinase conformations, Asp-Phe-Gly (DFG)-in and DFG-out, and three types of inhibitors, type I, II, and III, were thoroughly investigated in this work. We performed Brownian dynamics simulations and up to 340 us Gaussian-accelerated molecular dynamics simulations to capture the inhibitor binding paths and a series of conformational transitions of the p38 kinase from its apo to inhibitor-bound form. Eighteen successful binding trajectories, including all types of inhibitors, are reported herein. Our simulations suggest a mechanism of inhibitor recruitment, a faster ligand association step to a pre-existing DFG-in/DFG-out p38 protein, followed by a slower molecular rearrangement step to adjust the protein-ligand conformation followed by a shift in the energy landscape to reach the final bound state. The ligand association processes also reflect the energetic favor of type I and type II/111 inhibitor binding through ATP and allosteric channels, respectively. These different binding routes are directly responsible for the fast (type I binders) and slow (type II/III binders) kinetics of different types of p38 inhibitors. Our findings also echo the recent study of p38 inhibitor dissociation, implying that ligand unbinding could undergo a reverse path of binding, and both processes share similar metastates. This study deepens the understanding of molecular and energetic features of kinase inhibitor-binding processes and will inspire future drug development from a kinetic point of view.