Redistribution of flexibility in stabilizing antibody fragment mutants follows Le Châtelier's principle.
Redistribution of flexibility in stabilizing antibody fragment mutants follows Le Châtelier's principle.
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DOI：
10.1371/journal.pone.0092870
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Livesay DR
中科院分区：
文献类型：
--
作者：
Li T;Tracka MB;Uddin S;Casas-Finet J;Jacobs DJ;Livesay DR
勒chaltelier原理是我们理解化学平衡的基石。当处于平衡状态的系统发生浓度或热力学状态（即温度、压力等）的变化时，La chtelier原理指出，平衡位移将发生以抵消扰动，并建立新的平衡。我们证明了稳定突变对刚性的影响，在固有状态集合内的弹性平衡，当蛋白质结构调整以恢复两者之间的全局平衡时，通过焓-熵补偿表现出来。具体来说，我们使用计算距离约束模型来表征突变对抗淋巴毒素β受体抗体单链片段的影响。通常观察到分子结构中刚性和柔韧性分布的统计显著变化，其中局部扰动通常导致柔韧性和刚性分布的远端变化。然而，个体突变体灵活性的净增益或净损失是有偏差的。尽管所有的突变体在这个数据集中都是稳定的，但增加的灵活性比增加的刚性更常见。从机制上讲，弹性的再分配很大程度上是由氢键网络的变化控制的。例如，一个稳定突变可以引起局部刚性的增加，因为形成了新的氢键，同时在其他地方破坏氢键，导致通过Le chchtelier远离突变位点的灵活性增加。在VH β4/β5环内增加的灵活性是这种远程效应的一个值得注意的例证。
Le Châtelier’s principle is the cornerstone of our understanding of chemical equilibria. When a system at equilibrium undergoes a change in concentration or thermodynamic state (i.e., temperature, pressure, etc.), La Châtelier’s principle states that an equilibrium shift will occur to offset the perturbation and a new equilibrium is established. We demonstrate that the effects of stabilizing mutations on the rigidity ⇔ flexibility equilibrium within the native state ensemble manifest themselves through enthalpy-entropy compensation as the protein structure adjusts to restore the global balance between the two. Specifically, we characterize the effects of mutation to single chain fragments of the anti-lymphotoxin-β receptor antibody using a computational Distance Constraint Model. Statistically significant changes in the distribution of both rigidity and flexibility within the molecular structure is typically observed, where the local perturbations often lead to distal shifts in flexibility and rigidity profiles. Nevertheless, the net gain or loss in flexibility of individual mutants can be skewed. Despite all mutants being exclusively stabilizing in this dataset, increased flexibility is slightly more common than increased rigidity. Mechanistically the redistribution of flexibility is largely controlled by changes in the H-bond network. For example, a stabilizing mutation can induce an increase in rigidity locally due to the formation of new H-bonds, and simultaneously break H-bonds elsewhere leading to increased flexibility distant from the mutation site via Le Châtelier. Increased flexibility within the VH β4/β5 loop is a noteworthy illustration of this long-range effect.
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