Heterogeneous and rate-dependent streptavidin-biotin unbinding revealed by high-speed force spectroscopy and atomistic simulations
Heterogeneous and rate-dependent streptavidin-biotin unbinding revealed by high-speed force spectroscopy and atomistic simulations
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DOI：
10.1073/pnas.1816909116
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发表时间：
2019-04-02
影响因子：
11.1
通讯作者：
Scheuring, Simon
中科院分区：
文献类型：
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作者：
Rico, Felix;Russek, Andreas;Scheuring, Simon
受体-配体相互作用对生物功能至关重要，它们的结合强度通常用基于分子互补性的静态锁-键模型来解释。然而，由于原子结构的静态性质和整体生物物理学方法固有的集合平均，通常缺乏完整解结合途径的详细信息。在这里，我们结合分子动力学和高速力光谱对链霉亲和素-生物素复合物在最宽的动态范围内确定结合强度和解结合途径。实验和仿真结果表明，在重叠速度下，两者具有良好的一致性，并为解绑定机制提供了证据。在解结合过程中，生物素跨越多个能垒，并在远离结合袋的地方进入各种中间状态，而链霉亲和素则经历短暂的诱导拟合，所有这些都随着加载速率而变化。这种多态过程减缓了向非结合状态的转变，有利于重新结合，从而解释了复合体的长寿命。我们提供了一个原子的、动态的解结合过程的图像，用一个包含许多锁定途径和中间产物的速率相关诱导拟合运动的图像取代了一个简单的两态图像，这可能与其他受体-配体键有关。
Receptor-ligand interactions are essential for biological function and their binding strength is commonly explained in terms of static lock-and-key models based on molecular complementarity. However, detailed information on the full unbinding pathway is often lacking due, in part, to the static nature of atomic structures and ensemble averaging inherent to bulk biophysics approaches. Here we combine molecular dynamics and high-speed force spectroscopy on the streptavidin-biotin complex to determine the binding strength and unbinding pathways over the widest dynamic range. Experiment and simulation show excellent agreement at overlapping velocities and provided evidence of the unbinding mechanisms. During unbinding, biotin crosses multiple energy barriers and visits various intermediate states far from the binding pocket, while streptavidin undergoes transient induced fits, all varying with loading rate. This multistate process slows down the transition to the unbound state and favors rebinding, thus explaining the long lifetime of the complex. We provide an atomistic, dynamic picture of the unbinding process, replacing a simple two-state picture with one that involves many routes to the lock and rate-dependent induced-fit motions for intermediates, which might be relevant for other receptor-ligand bonds.