【摘 要】
：
人血白蛋白(HSA),是人血浆中含量最丰富的一种蛋白质,能与许多内源性和外源性化合物结合,是一种重要的存储和转运蛋白.HSA 主要有两个药物结合位点,位点I 和位点Ⅱ,许多小分子优先结合在位点Ⅱ上,例如抗炎类药物布洛芬(α-甲基-4-(2-甲基丙基)苯乙酸).本文采用分子模拟方法研究布洛芬小分子与HSA 位点Ⅱ 结合的动态过程,探讨二者的结合机制.首先构建了50 个随机分布的布洛芬与HSA 复合物
【机 构】
：
浙江大学化学工程与生物工程学院,杭州 310027
【出 处】
：
中国生物化学与分子生物学会2016年全国学术会议
论文部分内容阅读
人血白蛋白(HSA),是人血浆中含量最丰富的一种蛋白质,能与许多内源性和外源性化合物结合,是一种重要的存储和转运蛋白.HSA 主要有两个药物结合位点,位点I 和位点Ⅱ,许多小分子优先结合在位点Ⅱ上,例如抗炎类药物布洛芬(α-甲基-4-(2-甲基丙基)苯乙酸).本文采用分子模拟方法研究布洛芬小分子与HSA 位点Ⅱ 结合的动态过程,探讨二者的结合机制.首先构建了50 个随机分布的布洛芬与HSA 复合物体系,采用AMBER 软件进行50 ns 分子动力学模拟,发现一个布洛芬分子稳定结合于HSA 的位点Ⅱ.分析运动轨迹,发现布洛芬的结合可分为四个阶段,即远程吸引、表面结合调整、进入位点Ⅱ 空腔和稳定结合.比较范德华和静电相互作用能,发现初期以静电吸引为主,中期在HSA 表面的两个极性区域间波动,转移至位点Ⅱ 附近；然后在位点Ⅱ 入口处的极性残基和附近疏水残基的共同作用下,布洛芬进入位点Ⅱ空腔；进入空腔后,静电和疏水共同作用形成稳定结合.在结合过程中,位点Ⅱ附件的关键氨基酸残基波动较大,蛋白表面发生明显改变,通过动态调整促使布洛芬分子进入位点Ⅱ 空腔.比较发现,分子模拟得到的结合模式和布洛芬-HSA结合的晶体结构类似.结果表明,分子模拟可以用于探究小分子和蛋白结合的动态过程,深入了解结合过程的微观变化,从分子水平阐述结合机制,同时也可为特定位点的药物和分离配基设计提供指导.
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