Steric and Allosteric Effects of Fatty Acids on the Binding of Warfarin to Human Serum Albumin Revealed by Molecular Dynamics and Free Energy Calculations
Steric and Allosteric Effects of Fatty Acids on the Binding of Warfarin to Human Serum Albumin Revealed by Molecular Dynamics and Free Energy Calculations
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DOI：
10.1248/cpb.59.860
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发表时间：
2011-07-01
影响因子：
1.7
通讯作者：
Amisaki, Takashi
中科院分区：
文献类型：
--
作者：
Fujiwara, Shin-ichi;Amisaki, Takashi
人血清白蛋白 (HSA) 与药物和脂肪酸 (FA) 结合。本研究旨在阐明 HSA 的华法林结合亲和力与结合 FA 分子的位置之间的关系。对 11 种 HSA-华法林-肉豆蔻酸酯复合物进行了分子动力学模拟。然后通过分子力学-泊松-玻尔兹曼表面积（MM-PBSA）方法计算每个复合物的HSA-华法林结合自由能。结果表明，具有4个或更多肉豆蔻酸酯分子的HSA-华法林复合物中的结合自由能的大小比没有肉豆蔻酸酯分子的复合物中的结合自由能的大小更小。对 HSA-华法林结合亲和力的不利影响是由于肉豆蔻酸酯分子与最接近华法林结合位点的 FA 结合位点的结合而造成的。另一方面，当 3 个肉豆蔻酸酯分子与高亲和力位点结合时，HSA-华法林结合自由能的大小最大。最强的HSA-华法林结合归因于与华法林结合位点氨基酸残基较大原子波动相关的有利熵贡献。在 2 个肉豆蔻酸酯分子与具有最高和第二高亲和力的位点的结合中，观察到增强华法林与华法林结合位点周围的一些氨基酸残基之间的静电相互作用的变构调节。这项研究阐明了 FA 的空间/变构效应对 HSA-华法林结合亲和力的结构和能量特性，并说明了在多个配体与蛋白质其他位点结合的情况下分析蛋白质配体相互作用的方法。
Human serum albumin (HSA) binds with drugs and fatty acids (FAs). This study was initiated to elucidate the relationship between the warfarin binding affinity of HSA and the positions of bound FA molecules. Molecular dynamics simulations of 11 HSA-warfarin-myristate complexes were performed. HSA-warfarin binding free energy was then calculated for each of the complexes by the molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) method. The results indicated that the magnitude of the binding free energy was smaller in HSA-warfarin complexes that had 4 or more myristate molecules than in complexes with no myristate molecules. The unfavorable effect on the HSA-warfarin binding affinity was caused sterically by the binding of a myristate molecule to the FA binding site closest to the warfarin binding site. On the other hand, the magnitude of HSA-warfarin binding free energy was largest when 3 myristate molecules were bound to the high-affinity sites. The strongest HSA-warfarin binding was attributable to favorable entropic contribution related to larger atomic fluctuations of the amino acid residues at the warfarin binding site. In the binding of 2 myristate molecules to the sites with the highest and second-highest affinities, allosteric modulation that enhanced electrostatic interactions between warfarin and some of the amino acid residues around the warfarin binding site was observed. This study clarified the structural and energetic properties of steric/allosteric effects of FAs on the HSA-warfarin binding affinity and illustrated the approach to analyze protein ligand interactions in situations such that multiple ligands bind to the other sites of the protein.