Collective dynamics underlying allosteric transitions in hemoglobin.
Collective dynamics underlying allosteric transitions in hemoglobin.
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DOI：
10.1371/journal.pcbi.1003232
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发表时间：
2013
影响因子：
4.3
通讯作者：
de Groot BL
中科院分区：
文献类型：
--
作者：
Vesper MD;de Groot BL
血红蛋白是原型的变构蛋白。然而，其分子变构机制尚不完全清楚。为了在原子水平上阐明协同作用的机制，我们开发了一种新的计算技术来分析三级和四级运动的耦合。根据分子动力学模拟显示的自发季过渡，我们将过渡轨迹分为两组正交运动：一组仅由链内运动组成（仅称为叔代运动），另一组仅由全局链间运动组成（仅称为季代运动）。两个潜在的子空间通过构造是正交的，它们的直接和是完全运动的空间。利用功能模式分析，我们能够识别出第三系子空间中与第四纪运动中最主要运动相关的集体坐标，从而直接了解第三系和第四纪构象变化之间的变构耦合机制。这种耦合运动与T态和r态晶体结构之间的三级结构变化有本质的不同。我们发现血红蛋白亚基之间的变构通信机制同样基于氢键和空间相互作用。此外，我们能够通过选择不同的组氨酸质子化状态来影响t到r的转变速率，从而为玻尔效应提供了一种可能的原子解释。血红蛋白将氧气从肺部输送到其他组织。它在结合和解除氧结合方面的有效性是基于一种称为变构的调节。因此，在血红蛋白的四个结合位点中的任何一个上已经结合的氧分子增加了氧在其他位点结合的可能性；这些网站相互合作。众所周知，血红蛋白的四条蛋白链（每条蛋白链包含一个氧结合位点）需要在全局上重新排列，否则协同性就会丧失。但是在这种重排中，单个链是如何相互沟通的呢？这在分子水平上仍未得到解决。通过应用分子动力学模拟的计算技术，我们能够模拟血红蛋白在这种全局重排过程中的单个原子的运动。我们提出了一种新的方法，可以直接分析四个蛋白质链内部和之间的运动耦合，从而揭示变构机制。这使我们能够区分哪些氨基酸对协同作用是重要的，以及以何种方式：是将其他氨基酸推开还是吸引它们。此外，我们在模拟中观察到pH值的差异如何影响协同性。
Hemoglobin is the prototypic allosteric protein. Still, its molecular allosteric mechanism is not fully understood. To elucidate the mechanism of cooperativity on an atomistic level, we developed a novel computational technique to analyse the coupling of tertiary and quaternary motions. From Molecular Dynamics simulations showing spontaneous quaternary transitions, we separated the transition trajectories into two orthogonal sets of motions: one consisting of intra-chain motions only (referred to as tertiary-only) and one consisting of global inter-chain motions only (referred to as quaternary-only). The two underlying subspaces are orthogonal by construction and their direct sum is the space of full motions. Using Functional Mode Analysis, we were able to identify a collective coordinate within the tertiary-only subspace that is correlated to the most dominant motion within the quaternary-only motions, hence providing direct insight into the allosteric coupling mechanism between tertiary and quaternary conformation changes. This coupling-motion is substantially different from tertiary structure changes between the crystallographic structures of the T- and R-state. We found that hemoglobin's allosteric mechanism of communication between subunits is equally based on hydrogen bonds and steric interactions. In addition, we were able to affect the T-to-R transition rates by choosing different histidine protonation states, thereby providing a possible atomistic explanation for the Bohr effect. Hemoglobin transports oxygen from our lungs to other tissues. Its effectiveness in binding and unbinding of oxygen is based on a type of regulation called allostery. Thereby, already bound oxygen molecules in either of the four binding sites of hemoglobin increase the likelihood of oxygen binding in the other sites; the sites act cooperatively. It is known that the four protein chains of hemoglobin – each containing one oxygen binding site – need to rearrange globally or the cooperativity is lost. But how do the individual chains communicate with each other in this rearrangement? This is still not resolved on the molecular level. By applying the computational technique of molecular dynamics simulations we were able to simulate the motions of the individual atoms of hemoglobin during such a global rearrangement. We present a novel method that allows to directly analyse the coupling of motions within and between the four protein chains and thereby reveal the allosteric mechanism. That allows us to classify which amino acids are important for the cooperativity and in what way: by either pushing other amino acids away or attracting them. Also, we have observed in simulations how pH differences could affect the cooperativity.
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