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首页> 外文期刊>The journal of physical chemistry, B. Condensed matter, materials, surfaces, interfaces & biophysical >Cluster Size and Quinary Structure Determine the Rheological Effects of Antibody Self-Association at High Concentrations
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Cluster Size and Quinary Structure Determine the Rheological Effects of Antibody Self-Association at High Concentrations

机译：簇尺寸和静态结构决定了高浓度抗体自我关联的流变效应

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The question of how nonspecific reversible intermolecular protein interactions affect solution rheology at high concentrations is fundamentally rooted in the translation of nanometer-scale interactions into macroscopic properties. Well-defined solutions of purified monoclonal antibodies (mAbs) provide a useful system with which to investigate the manifold intricacies of weak protein interactions at high concentrations. Recently, characterization of self-associating IgG1 antibody (mAb2) solutions has established the direct role of protein clusters on concentrated mAb rheology. Expanding on our earlier work with three additional mAbs (rnAbl, mAb3, and mAb4), the observed concentration-dependent static light scattering and rheological data present a substantially more complex relationship between protein interactions and solution viscosity at high concentrations. The four mAb systems exhibited divergent correlations between cluster formation (size) and concentrated solution viscosities dependent on mAb primary sequence and solution conditions. To address this challenge, well established features of colloidal cluster phenomena could be applied as a framework for interpreting our observations. The initial stages of mAb cluster formation were investigated with small-angle X-ray scattering (SAXS) and ensemble-optimized fit methods, to uncover shifts in the dimer structure populations which are produced by changes in mAb interaction modes and association valence under the different solution conditions. Analysis of mAb average cluster number and effective hydrodynamic radii at high concentrations revealed cluster architectures can have a wide range of fractal dimensions. Collectively, the static light scattering, SAXS, and rheological characterization demonstrate that nonspecific and anisotropic attractive intermolecular interactions produce antibody clusters with different quinary structures to regulate the rheological properties of concentrated mAb solutions.
机译：非特异性可逆分子间蛋白质相互作用在高浓度下影响溶液流变的问题是基本上植根于纳米级相互作用转化为宏观性质的转化。纯化的单克隆抗体（MAb）的定义溶液提供了一种有用的系统，用于研究高浓度的弱蛋白质相互作用的歧管复杂性。最近，自相关IGG1抗体（MAB2）溶液的表征已经建立了蛋白质簇对浓缩MAB流变学的直接作用。在我们之前的三个额外的MAB（RNabk，MAB3和MAB4）上进行扩展，观察到的浓度依赖性静态光散射和流变数据在高浓度下呈现蛋白质相互作用和溶液粘度之间的基本更复杂的关系。四种MAB系统在依赖于MAB初级序列和溶液条件之间表现出簇形成（尺寸）和浓缩溶液粘度之间的发散相关性。为了解决这一挑战，胶体聚类现象的成熟特征可以作为解释我们观察的框架。研究了MAB簇形成的初始阶段，用小角度X射线散射（SAX）和集合优化的拟合方法来研究二聚体结构群中的换档，其通过不同的MAB交互模式和相关价值下的变化产生解决方案条件。在高浓度下，MAB平均聚类簇数和有效流体动力半径的分析显示群体架构可以具有各种分形尺寸。统称，静态光散射，萨克斯和流变特征表明，非特异性和各向异性的分子间分子相互作用产生具有不同樟脑结构的抗体簇，以调节浓缩MAB溶液的流变性质。

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