On the nature of the multivalency effect: A thermodynamic model
On the nature of the multivalency effect: A thermodynamic model
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DOI：
10.1021/ja038223n
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发表时间：
2003-12-31
影响因子：
15
通讯作者：
Bundle, DR
中科院分区：
文献类型：
--
作者：
Kitov, PI;Bundle, DR
提出了一个定量模型，用于分析稀溶液中多价相互作用的热力学参数或与固定化多聚体受体的相互作用。该模型考虑到所有结合的物种，并通过两个微观结合能对应于分子间和分子内的相互作用（DeltaGdegrees（间）和DeltaGdegrees（内）），其相对贡献取决于不同数量的占用结合位点的复合物的分布描述多价结合。总自由能的第三个组成部分，我们称之为“亲合力熵”项，是束缚态简并度的函数，Omega（i），它是根据相互作用的拓扑结构和所有束缚物种的分布计算的。这个术语随着受体位点和配体多价性的数量迅速增长，它总是有利于结合，并解释了为什么多价性可以克服长链末端显示的配体结合时构象熵的损失。微观参数DeltaGdegrees（inter）和DeltadegreesG（intra）可以通过与理论模型的非线性拟合从观察到的一组寡价配体的结合能确定。在这里，从两个系列的寡价碳水化合物抑制剂志贺样毒素的结合数据来验证的理论。十价和八价抑制剂表现出亚纳摩尔的活性，并且是迄今为止发现的阻断志贺样毒素与其天然受体结合的最有效的可溶性抑制剂。在这里开发的理论与我们的方案的优化系链长度提供了一个预测的方法来设计和最大限度地提高多价配体的亲和力。
A quantitative model is proposed for the analysis of the thermodynamic parameters of multivalent interactions in dilute solutions or with immobilized multimeric receptor. The model takes into account all bound species and describes multivalent binding via two microscopic binding energies corresponding to inter- and intramolecular interactions (DeltaGdegrees(inter) and DeltaGdegrees(intra)), the relative contributions of which depend on the distribution of complexes with different numbers of occupied binding sites. The third component of the overall free energy, which we call the "avidity entropy" term, is a function of the degeneracy of bound states, Omega(i), which is calculated on the basis of the topology of interaction and the distribution of all bound species. This term grows rapidly with the number of receptor sites and ligand multivalency, it always favors binding, and explains why multivalency can overcome the loss of conformational entropy when ligands displayed at the ends of long tethers are bound. The microscopic parameters DeltaGdegrees(inter) and DeltadegreesG(intra) may be determined from the observed binding energies for a set of oligovalent ligands by nonlinear fitting with the theoretical model. Here binding data obtained from two series of oligovalent carbohydrate inhibitors for Shiga-like toxins were used to verify the theory. The decavalent and octavalent inhibitors exhibit subnanomolar activity and are the most active soluble inhibitors yet seen that block Shiga-like toxin binding to its native receptor. The theory developed here in conjunction with our protocol for the optimization of tether length provides a predictive approach to design and maximize the avidity of multivalent ligands.