New insights into the allosteric mechanism of human hemoglobin from molecular dynamics simulations
New insights into the allosteric mechanism of human hemoglobin from molecular dynamics simulations
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DOI：
10.1016/s0006-3495(02)75665-8
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发表时间：
2002-06-01
影响因子：
3.4
通讯作者：
Guilbert, C
中科院分区：
文献类型：
--
作者：
Mouawad, L;Perahia, D;Guilbert, C
尽管进行了大量的实验研究，但仍然难以获得人血红蛋白的脱氧T-状态和氧合R-状态构象之间的转变的精确结构描述。我们使用分子动力学与距离约束的路径探索（PEDC）方法，通过模拟T-to-R转变，在原子水平上提供了对变构机制的新见解。在没有配体的情况下，T-状态分子被认为具有晚餐旋转的天然倾向，然而这将受到“关节”区域中的空间位阻的阻碍。配体与α亚基的结合将防止由于该区域与α近端组氨酸之间的偶联而引起的这种阻碍，从而促进二聚体旋转的完成。在这个四级转换的末端附近，“开关”区域采用R构象，导致β近端组氨酸的移位。这导致β-血红素的滑动，其效果是打开β-血红素的远端，增加Fe原子的可接近性，从而增加蛋白质的亲和力。我们的模拟是全球一致的Perutz streeochemical机制。
It is still difficult to obtain a precise structural description of the transition between the deoxy T-state and oxy R-state conformations of human hemoglobin, despite a large number of experimental studies. We used molecular dynamics with the Path Exploration with Distance Constraints (PEDC) method to provide new insights into the allosteric mechanism at the atomic level, by simulating the T-to-R transition. The T-state molecule in the absence of ligands was seen to have a natural propensity for dinner rotation, which nevertheless would be hampered by steric hindrance in the "joint" region. The binding of a ligand to the alpha subunit would prevent such hindrance due to the coupling between this region and the a proximal histidine, and thus facilitate completion of the dimer rotation. Near the end of this quaternary transition, the "switch" region adopts the R conformation, resulting in a shift of the beta proximal histidine. This leads to a sliding of the beta-heme, the effect of which is to open the beta-heme's distal side, increasing the accessibility of the Fe atom and thereby the affinity of the protein. Our simulations are globally consistent with the Perutz strereochemical mechanism.