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首页> 外文期刊>Biopolymers: Original Research on Biomolecules and Biomolecular Assemblies >Exploration of Human Serum Albumin Binding Sites by Docking and Molecular Dynamics Flexible Ligand-Protein Interactions
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Exploration of Human Serum Albumin Binding Sites by Docking and Molecular Dynamics Flexible Ligand-Protein Interactions

机译：对接和分子动力学柔性配体-蛋白质相互作用探索人血清白蛋白结合位点

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摘要

Five-nanosecond molecular dynamics (MD) simulations were performed on human serum albumin (HSA) to study the conformational features of its primary ligand binding sites (I and II). Additionally, II HSA snapshots were extracted every 0.5 ns to explore the binding affinity (K-d) of 94 known HSA binding drugs using a blind docking procedure. MD simulations indicate that there is considerable flexibility for the protein, including the known sites I and II. Movements at HSA sites I and II were evidenced by structural analyses and docking simulations. The latter enabled the study and analysis of the HSA-ligand interactions of warfarin and ketoprofen (ligands binding to sites I and II, respectively) in greater detail. Our results indicate that the free energy values by docking (Kd observed) depend upon the conformations of both HSA and the ligand. The 94 HSA-ligand binding Kd values, obtained by the docking procedure, were subjected to a quantitative structure-activity relationship (QSAR) study by multiple regression analysis. The best correlation between the observed and QSAR theoretical (K-d predicted) data was displayed at 2.5 ns. This study provides evidence that HSA binding sites I and II interact specifically with a variety of compounds through conformational adjustments of the protein structure in conjunction with ligand conformational adaptation to these sites. These results serve to explain the high ligand-promiscuity of HSA.
机译：在人血清白蛋白（HSA）上进行了5纳秒分子动力学（MD）模拟，以研究其主要配体结合位点（I和II）的构象特征。此外，每隔0.5 ns提取一次II HSA快照，以使用盲对接程序探索94种已知HSA结合药物的结合亲和力（K-d）。 MD模拟表明该蛋白质具有相当大的灵活性，包括已知的位点I和II。结构分析和对接模拟证明了HSA I和II站点的运动。后者使得能够更详细地研究和分析华法林与酮洛芬的HSA-配体相互作用（配体分别与部位I和部位II结合）。我们的结果表明对接的自由能值（观察到的Kd）取决于HSA和配体的构象。通过对接程序获得的94个HSA-配体结合Kd值，通过多元回归分析进行了定量结构-活性关系（QSAR）研究。在2.5 ns处显示了观测到的和QSAR理论（K-d预测）数据之间的最佳相关性。这项研究提供的证据表明，HSA结合位点I和II通过蛋白质结构的构象调整以及对这些位点的配体构象适应性，与多种化合物发生特异性相互作用。这些结果有助于解释HSA的高配体混杂性。

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