物理化学学报 >> 2016, Vol. 32 >> Issue (7): 1819-1828.doi: 10.3866/PKU.WHXB201604151

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人血白蛋白结合位点Ⅱ的分子结合模式研究

徐诗文,林东强*(),姚善泾   

  • 收稿日期:2016-01-18 发布日期:2016-07-08
  • 通讯作者: 林东强 E-mail:lindq@zju.edu.cn
  • 基金资助:
    国家自然科学基金(21476198);国家自然科学基金(21276228);国家自然科学基金(21576233)

Evaluation of Molecular Binding Modes on Site Ⅱ of Human Serum Albumin

Shi-Wen XU,Dong-Qiang LIN*(),Shan-Jing YAO   

  • Received:2016-01-18 Published:2016-07-08
  • Contact: Dong-Qiang LIN E-mail:lindq@zju.edu.cn
  • Supported by:
    the National Natural Science Foundation of China(21476198);National Natural Science Foundation of China(21276228);National Natural Science Foundation of China(21576233)

摘要:

人血白蛋白是血浆中含量最高的蛋白,是一种重要的载体蛋白,能与多种内源性和外源性物质结合。人血白蛋白主要有两个药物结合位点,位点Ⅰ和位点人血白蛋白结合位点Ⅱ的分子结合模式研究,其中位点Ⅱ的柔性较大,对药物分子的亲和性较高。本文采用分子模拟方法,基于12种结合于位点人血白蛋白结合位点Ⅱ的分子结合模式研究的小分子-人血白蛋白晶体结构,分析了相互作用能,发现12种分子的结合以疏水作用为主,静电作用为辅。进一步采用丙氨酸扫描和结合能评价,分析结合部位的关键氨基酸残基,探究结合模式的规律性,发现从位点入口到空腔内部存在静电、疏水和杂合的三层相互作用分布,共同形成了稳定的分子结合。最后采用分子对接和分子动力学模拟,预测了L-色氨酸的结合模式。研究结果有助于深入了解人血白蛋白药物位点Ⅱ的小分子结合模式,为基于位点Ⅱ的药物和分离配基的优化设计提供指导。

关键词: 人血白蛋白, 位点II, 分子对接, 分子动力学, 结合模式

Abstract:

Human serum albumin (HSA) is an extracellular protein that has the highest concentration in blood plasma and is a carrier for many small molecules. HSA has an exceptional binding capacity for many endogenous and exogenous ligands, and contains two main binding sites with high affinity for diverse substances, named Site Ⅰ and Site Ⅱ. The binding cavity of Site Ⅱ is more active and has greater ligand affinity than that of Site Ⅰ. In this study, molecular simulation methods were used to investigate the molecular interactions between Site Ⅱ and twelve Site Ⅱ-specific ligands. The results showed that hydrophobic interactions were the main driving force for binding, with electrostatic interactions playing a secondary role. The key residues and binding mode on Site Ⅱ were identified with the computational alanine-scanning approach. Three layers were found from the entrance to the interior of the binding pocket, contributing electrostatic interactions, hydrophobic interactions and mixed interactions, respectively. Finally, molecular docking and molecular dynamics were used to predict the binding mode of L-tryptophan on Site Ⅱ. The results provided insights into the binding mode of Site Ⅱ on HSA, which could guide the design of new Site Ⅱ-specific drugs and ligands for the efficient separation of HSA.

Key words: Human serum albumin, Site Ⅱ, Molecular docking, Molecular dynamics, Binding mode

MSC2000: 

  • O641