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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Dynamic force spectroscopy of parallel individual Mucin1-antibody bonds.
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Dynamic force spectroscopy of parallel individual Mucin1-antibody bonds.

机译：平行的单个Mucin1-抗体键的动态力谱。

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摘要

We used atomic force microscopy to measure the binding forces between Mucin1 (MUC1) peptide and a single-chain variable fragment (scFv) antibody selected from a scFv library screened against MUC1. This binding interaction is central to the design of molecules used for targeted delivery of radioimmunotherapeutic agents for prostate and breast cancer treatment. Our experiments separated the specific binding interaction from nonspecific interactions by tethering the antibody and MUC1 molecules to the atomic force microscope tip and sample surface with flexible polymer spacers. Rupture force magnitude and elastic characteristics of the spacers allowed identification of the rupture events corresponding to different numbers of interacting proteins. We used dynamic force spectroscopy to estimate the intermolecular potential widths and equivalent thermodynamic off rates for monovalent, bivalent, and trivalent interactions. Measured interaction potential parameters agree with the results of molecular docking simulation. Our results demonstrate that an increase of the interaction valency leads to a precipitous decline in the dissociation rate. Binding forces measured for monovalent and multivalent interactions match the predictions of a Markovian model for the strength of multiple uncorrelated bonds in a parallel configuration. Our approach is promising for comparison of the specific effects of molecular modifications as well as for determination of the best configuration of antibody-based multivalent targeting agents.
机译：我们使用原子力显微镜来测量Mucin1（MUC1）肽和单链可变片段（scFv）抗体之间的结合力，该抗体选自针对MUC1筛选的scFv库。这种结合相互作用对于用于靶向递送放射免疫治疗剂以治疗前列腺癌和乳腺癌的分子的设计至关重要。我们的实验通过使用柔性聚合物间隔子将抗体和MUC1分子束缚到原子力显微镜尖端和样品表面，从而将特异性结合相互作用与非特异性相互作用分开。间隔物的断裂力大小和弹性特征允许鉴定对应于不同数量的相互作用蛋白的断裂事件。我们使用动态力光谱法来估计单价，二价和三价相互作用的分子间电位宽度和等效热力学解离速率。测得的相互作用势参数与分子对接模拟的结果一致。我们的结果表明，相互作用价的增加导致解离速率的急剧下降。对于单价和多价相互作用测得的结合力与马尔可夫模型中平行构型中多个不相关键的强度的预测相符。我们的方法有望用于比较分子修饰的特定作用以及确定基于抗体的多价靶向剂的最佳构型。

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