Understanding the Stabilizing Effect of Histidine on mAb Aggregation: A Molecular Dynamics Study.
Understanding the Stabilizing Effect of Histidine on mAb Aggregation: A Molecular Dynamics Study.
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DOI：
10.1021/acs.molpharmaceut.2c00453
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发表时间：
2022-09-05
影响因子：
4.9
通讯作者：
Bresme, Fernando
中科院分区：
文献类型：
--
作者：
Saurabh, Suman;Kalonia, Cavan;Li, Zongyi;Hollowell, Peter;Waigh, Thomas;Li, Peixun;Webster, John;Seddon, John M.;Lu, Jian R.;Bresme, Fernando
关键词：
组氨酸是一种在单抗配方中广泛使用的缓冲液，众所周知，它可以减少抗体聚集。虽然实验研究表明这种现象是非静电的、非结构性的(与二级结构保存有关)，但组氨酸作用背后的潜在微观机制仍不清楚。了解这一机制将有助于评估和预测该缓冲液在不同实验条件下对不同单抗的稳定效果。我们使用全原子分子动力学模拟和基于接触的自由能计算来研究组氨酸缓冲液和单抗之间的分子水平相互作用，这导致在组氨酸存在的情况下观察到的治疗配方的稳定性。我们重新定义了空间聚集倾向指数，包括了缓冲-蛋白质相互作用。蛋白质表面的缓冲吸附导致疏水性区域在水中的暴露程度较低。我们的分析表明，组氨酸稳定作用背后的机制与缓冲分子屏蔽蛋白质表面暴露在溶剂中的疏水性区域有关。
Histidine, a widely used buffer in monoclonal antibody (mAb) formulations, is known to reduce antibody aggregation. While experimental studies suggest a nonelectrostatic, nonstructural (relating to secondary structure preservation) origin of the phenomenon, the underlying microscopic mechanism behind the histidine action is still unknown. Understanding this mechanism will help evaluate and predict the stabilizing effect of this buffer under different experimental conditions and for different mAbs. We have used all-atom molecular dynamics simulations and contact-based free energy calculations to investigate molecular-level interactions between the histidine buffer and mAbs, which lead to the observed stability of therapeutic formulations in the presence of histidine. We reformulate the Spatial Aggregation Propensity index by including the buffer–protein interactions. The buffer adsorption on the protein surface leads to lower exposure of the hydrophobic regions to water. Our analysis indicates that the mechanism behind the stabilizing action of histidine is connected to the shielding of the solvent-exposed hydrophobic regions on the protein surface by the buffer molecules.
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