Key Laboratory for Microstructural Material Physics of Hebei Province, College of Science, Yanshan University, Qinhuangdao 066004, China.
College of Life Science and Bioengineering, Beijing University of Technology, Beijing 100124, China.
J Chem Phys. 2019 Apr 21;150(15):155102. doi: 10.1063/1.5054932.
As revealed by previous experiments, protein mechanical stability can be effectively regulated by ligand binding with the binding site distant from the force-bearing region. However, the mechanism for such long-range allosteric control of protein mechanics is still largely unknown. In this work, we use protein topology-based elastic network model (ENM) and all-atomic steered molecular dynamics (SMD) simulations to study the impact of ligand binding on protein mechanical stability in two systems, i.e., GB1 and CheY-binding P2-domain of CheA (CBDCheA). Both ENM and SMD results show that the ligand binding has considerable and negligible effects on the mechanical stability of these two proteins, respectively. These results are consistent with the experimental observations. A physical mechanism for the enhancement of protein mechanical stability was then proposed: the correlated deformations of the force-bearing region and the binding site are handcuffed by the binding of ligand. The handcuff effect suppresses the propagation of internal force in the force-bearing region, thus improving the resistance to the loading force. Our study indicates that ENM method can effectively identify the structure motifs allosterically related to the deformation in the force bearing region, as well as the force propagation pathway within the structure of the studied proteins. Hence, it should be helpful to understand the molecular origin of the different mechanical properties in response to ligand binding for GB1 and CBDCheA.
如先前的实验所揭示的，蛋白质的机械稳定性可以通过与远离受力区域的结合位点结合的配体有效地调节。然而，这种长程变构控制蛋白质力学的机制在很大程度上仍然未知。在这项工作中，我们使用基于蛋白质拓扑的弹性网络模型（ENM）和全原子导向分子动力学（SMD）模拟来研究配体结合对两种系统（即 GB1 和 CheA 的 CheY 结合 P2 结构域（CBDCheA））中蛋白质机械稳定性的影响。ENM 和 SMD 的结果均表明，配体结合分别对这两种蛋白质的机械稳定性有相当大的和可忽略的影响。这些结果与实验观察结果一致。然后提出了一种增强蛋白质机械稳定性的物理机制：配体结合将受力区域和结合位点的相关变形束缚在一起。手铐效应抑制了受力区域内力的传播，从而提高了抵抗加载力的能力。我们的研究表明，ENM 方法可以有效地识别与受力区域变形相关的结构模体，以及研究蛋白质内部的力传播途径。因此，它应该有助于理解 GB1 和 CBDCheA 对配体结合的不同机械性能的分子起源。
