Molecular dynamics study of the IIA binding site in human serum albumin:: Influence of the protonation state of Lys195 and Lys199
Molecular dynamics study of the IIA binding site in human serum albumin:: Influence of the protonation state of Lys195 and Lys199
复制标题
DOI：
10.1021/jm000340v
复制
发表时间：
2001-01-18
影响因子：
7.3
通讯作者：
Merz, KM
中科院分区：
文献类型：
--
作者：
Díaz, N;Suárez, D;Merz, KM
人血清白蛋白（HSA）的IIA结合位点优先结合中等大小的疏水性有机阴离子（例如阿司匹林、青霉素、华法林等）和胆红素。这种结合能力对于药物的分布、代谢和功效尤其重要。此外，由于存在高度反应性残基 Lys199（战略性地位于 IIA 位点），HSA 还可以与不同的 IIA 底物共价连接。在此，我们展示了 HSA 蛋白上 IIA 结合位点的三个受限分子动力学 (MD) 模拟结果。从这些模拟中，我们确定了关键残基 Lys199 和附近的 Lys195 的电离态对 IIA 结合位点的结构和动力学的影响。当 Lys199 为中性时，计算出的最显着残基间接触的平均距离与根据 X 射线坐标估计的距离非常一致。溶剂结构和动力学分析表明，Lys199 的基本形式可能通过具有供体 --> 受体特征的氢键水分子网络与 Lys195 的酸形式连接。这些水桥的存在对于稳定 IIA 结合位点的构型和/或促进潜在的 Lys195 --> Lys199 质子转移过程非常重要。这些结果表明，位于 HSA IIA 结合位点的两个赖氨酸残基 Lys195 和 Lys199 可以发挥组合且可比较的化学作用。我们的模拟还深入了解了胆红素与 HSA 的结合。
The IIA binding site of human serum albumin (HSA) preferentially binds hydrophobic organic anions of medium size (e.g., aspirin, benzylpenicillin, warfarin, etc.) and bilirubin. This binding ability is particularly important for the distribution, metabolism, and efficacy of drugs. In addition, HSA can also covalently link to different IIA substrates owing to the presence of a highly reactive residue, Lys199, which is strategically located in the IIA site. Herein, we present results of three restrained molecular dynamics (MD) simulations of the IIA binding site on the HSA protein. From these simulations, we have determined the influence that the ionization state of the key residue, Lys199, and the nearby Lys195 has on the structure and dynamics of the IIA binding site. When Lys199 is neutral the computed average distances for the most significant interresidue contacts are in good agreement with those estimated from the X-ray coordinates. The analysis of the solvent structure and dynamics indicates that the basic form of Lys199 is likely connected to the acid form of Lys195 through a network of H-bonding water molecules with a donor --> acceptor character. The presence of these, water bridges can be important for stabilizing the configuration of the IIA binding site and/or promoting a potential Lys195 --> Lys199 proton-transfer process. These results suggest that both lysine residues located in the IIA binding site of HSA, Lys195 and Lys199, could play a combined and comparable chemical role. Our simulations also give insight into the binding of bilirubin to HSA.