Laboratoire Adhésion et Inflammation (LAI), Aix-Marseille Université, CNRS, INSERM, 13009 Marseille, France;
Department of Theoretical and Computational Biophysics, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
Proc Natl Acad Sci U S A. 2019 Apr 2;116(14):6594-6601. doi: 10.1073/pnas.1816909116. Epub 2019 Mar 19.
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.
受体-配体相互作用对于生物功能至关重要，其结合强度通常可以根据分子互补性的静态锁钥模型来解释。然而，由于原子结构的静态性质和体相生物物理学方法固有的整体平均化，通常缺乏关于完整解吸途径的详细信息。在这里，我们结合分子动力学和高速力谱法研究了链霉亲和素-生物素复合物，以确定在最宽的动态范围内的结合强度和解吸途径。实验和模拟在重叠速度下表现出极好的一致性，并提供了解吸机制的证据。在解吸过程中，生物素穿过多个能量势垒并访问远离结合口袋的各种中间状态，而链霉亲和素经历瞬态诱导契合，所有这些都随加载速率而变化。这个多态过程减缓了向非结合状态的转变，并有利于重新结合，从而解释了复合物的长寿命。我们提供了解吸过程的原子动态图像，用涉及到许多锁定途径和速率相关的中间态诱导契合运动的图像取代了简单的两态图像，这可能与其他受体-配体键有关。
