Exploration of gated ligand binding recognizes an allosteric site for blocking FABP4-protein interaction.
Exploration of gated ligand binding recognizes an allosteric site for blocking FABP4-protein interaction.
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DOI：
10.1039/c5cp04784f
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发表时间：
2015-12-28
期刊：
影响因子：
--
通讯作者：
Dong Z
中科院分区：
文献类型：
--
作者：
Li Y;Li X;Dong Z
脂肪酸结合蛋白4（FABP 4）与脂肪酸和其他脂质具有高亲和力可逆结合，是治疗癌症的潜在靶点。FABP 4的结合位点被埋在内腔中，从而配体结合/解结合与FABP 4的打开/关闭偶联。无论在实验上还是在计算上，都很难阐明进入或退出途径，尤其是构象门控。在这份报告中，我们结合联合收割机广泛的计算机模拟，聚类分析，和马尔可夫状态模型来研究FABP 4和曲格列酮的结合机制。我们的模拟捕捉自发的结合和解结合的事件，以及开放和封闭状态之间的FABP 4的构象转变。蛋白质表面上的变构结合位点被认为用于开发新型FABP 4抑制剂。结合亲和力的计算和比较与实验值。动力学分析表明，配体驻留在蛋白质表面可能会延迟结合过程。总的来说，我们的研究结果提供了一个全面的图片配体在蛋白质表面上的扩散，配体迁移到掩埋腔，和构象变化的FABP 4在原子水平上。
Fatty acid binding protein 4 (FABP4), reversibly binding to fatty acids and other lipids with high affinities, is a potential target for treatment of cancers. The binding site of FABP4 is buried in an interior cavity and thereby ligand binding/unbinding is coupled with opening/closing of FABP4. It is a difficult task both experimentally and computationally to illuminate the entry or exit pathway, especially with the conformational gating. In this report we combine extensive computer simulations, clustering analysis, and Markov state model to investigate the binding mechanism of FABP4 and troglitazone. Our simulations capture spontaneous binding and unbinding events as well as the conformational transition of FABP4 between the open and closed states. An allosteric binding site on the protein surface is recognized for development of novel FABP4 inhibitors. The binding affinity is calculated and compared with the experimental value. The kinetic analysis suggests that ligand residence on the protein surface may delay the binding process. Overall, our results provide a comprehensive picture of ligand diffusion on the protein surface, ligand migration into the buried cavity, and the conformational change of FABP4 at an atomic level.