Protein dynamics explain the allosteric behaviors of hemoglobin.
Protein dynamics explain the allosteric behaviors of hemoglobin.
复制标题
DOI：
10.1016/j.bbapap.2008.04.025
复制
发表时间：
2008-09
期刊：
影响因子：
--
通讯作者：
T. Yonetani;M. Laberge
中科院分区：
文献类型：
--
作者：
T. Yonetani;M. Laberge
Bohr、Hasselbalch和Krogh在1903/1904年发现了血红蛋白（Hb）的同变构和异变构行为。简要介绍了自那时以来选定的主要模型，如Adair方案，MWC两状态协调模型，KNF诱导拟合顺序模型，Perutz立体化学模型，三级两状态模型，和全球变构模型（一个扩展的MWC模型）的时间顺序，然后分析和讨论其局限性和不足。Perutz对脱氧血红蛋白和连接血红蛋白的X射线晶体结构的测定以及基于结构的立体化学模型是这一历史上划时代的事件。然而，他将血红蛋白的低亲和力脱氧和高亲和力氧四级结构分别分配给T-和R-状态，尽管显然是合理的，以及他的T-/R-四级结构转变调节氧亲和力的假设，已经造成了混乱和对血红蛋白结构-功能关系的偏离研究。Perutz和其他人详细报道的T（脱氧）-和R（氧）-四级状态之间Hb静态分子结构的差异是连接连接的结构变化，但与氧亲和力的控制/调节无关。血红蛋白的氧亲和力（KT和KR）已被证明是由异嗜性效应相关的三级结构的变化，而不涉及T/R-四级的变化。然而，最近的高分辨率晶体学分析的血红蛋白与不同的氧亲和性表明，静态的血红蛋白的分子结构确定的晶体学既不能识别的T（低亲和力）功能状态的性质，也不能破译的机制，血红蛋白存储自由能在T（低亲和力）功能状态。分子动力学模拟表明，脱氧和/或结合2，3-二磷酸甘油酸后，oxy-Hb的螺旋波动增加。已知这些降低Hb的氧亲和力。有人提出，这些螺旋波动调节了血红素Fe与近端和远端His的配位模式，从而调节了Hb的氧亲和力。因此，它是建议，血红蛋白的氧亲和力是由五元（5阶的时间依赖性或动态）的三级结构变化，而不是T-/R-的四元结构转换在血红蛋白的调节。血红蛋白的同变和异变变构效应是与氧和效应子相关的、构象熵驱动的熵-焓补偿现象，与静态结构变化关系不大。动态变构模型，它集成了这些观察，提供了结构基础的全球变构模型（扩展MWC模型）。
Bohr, Hasselbalch, and Krogh discovered homotropic and heterotropic allosteric behaviors of hemoglobin (Hb) in 1903/1904. A chronological description since then of selected principal models of the allosteric mechanism of Hb, such as the Adair scheme, the MWC two-state concerted model, the KNF induced-fit sequential model, the Perutz stereochemical model, the tertiary two-state model, and the global allostery model (an expanded MWC models), is concisely presented, followed by analysis and discussion of their limitations and deficiencies. The determination of X-ray crystallographic structures of deoxy- and ligated-Hb and the structure-based stereochemical model by Perutz are an epoch-making event in this history. However, his assignment of low-affinity deoxy- and high-affinity oxy-quaternary structures of Hb to the T- and R-states, respectively, though apparently reasonable, and as well as his hypothesis that the T-/R-quaternary structural transition regulates the oxygen-affinity, have created confusions and side-tracked studies of Hb on the structure–function relationship. The differences in static molecular structures of Hb between T(deoxy)- and R(oxy)-quaternary states reported in detail by Perutz and others are ligation-linked structural changes, but not related to the control/regulation of the oxygen-affinity. The oxygen-affinity (KTand KR) of Hb has been shown to be regulated by the heterotropic effector-linked tertiary structural changes without involving the T/R-quaternary changes. However, a recent high-resolution crystallographic analysis of Hb with different oxygen-affinities shows that static molecular structures of Hb determined by crystallography can neither identify the nature of the T(low-affinity) functional state nor decipher the mechanism by which Hb stores free energy in the T(low-affinity) functional state. Molecular dynamics simulations show that fluctuations of helices of oxy-Hb are increased upon de-oxygenation and/or binding 2,3-biphosphoglycerate. These are known to lower the oxygen-affinity of Hb. It is proposed that the coordination mode of the heme Fe with proximal and distal His is modulated by these helical fluctuations, resulting in the modulation of the oxygen-affinity of Hb. Therefore, it is proposed that the oxygen-affinity of Hb is regulated by pentanary (the 5th-order time-dependent or dynamic) tertiary structural changes rather than the T-/R-quaternary structural transitions in Hb. Homotropic and heterotropic allosteric effects of Hb are oxygen- and effector-linked, conformational entropy-driven entropy-enthalpy compensation phenomena and not much to do with static structural changes. The dynamic allostery model, which integrates these observations, provides the structural basis for the global allostery model (an expanded MWC model).