Sun Hao, Guo Zilong, Hong Haiyan, Zhang Zhuwei, Zhang Yuhang, Wang Yang, Le Shimin, Chen Hu
Research Institute for Biomimetics and Soft Matter, Fujian Provincial Key Lab for Soft Functional Materials Research, Department of Physics, Xiamen University, Xiamen 361005, China.
Center of Biomedical Physics, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou 325000, China.
Phys Rev Lett. 2023 Nov 24;131(21):218402. doi: 10.1103/PhysRevLett.131.218402.
The tenth domain of type III fibronectin (FNIII_{10}) mediates cell adhesion to the extracellular matrix. Despite its structural similarity to immunoglobulin domains, FNIII_{10} exhibits unique unfolding behaviors. We employed magnetic tweezers to investigate the unfolding and folding dynamics of FNIII_{10} under physiological forces (4-50 pN). Our results showed that FNIII_{10} follows a consistent transition pathway with an intermediate state characterized by detached A and G β strands. We determined the folding free energies and all force-dependent transition rates of FNIII_{10} and found that both unfolding rates from the native state to the intermediate state and from the intermediate state to the unfolded state deviate from Bell's model. We constructed a quantitative free energy landscape with well-defined traps and barriers that exhibits a hierarchical symmetrical pattern. Our findings provide a comprehensive understanding of FNIII_{10} conformational dynamics and demonstrate how free energy landscape of multistate biomolecules can be precisely mapped, illuminating the relationship between thermal stability, intermediate states, and folding rates in protein folding.
III型纤连蛋白的第十个结构域（FNIII₁₀）介导细胞与细胞外基质的黏附。尽管FNIII₁₀在结构上与免疫球蛋白结构域相似，但其展现出独特的解折叠行为。我们使用磁镊来研究生理力（4 - 50皮牛）作用下FNIII₁₀的解折叠和折叠动力学。我们的结果表明，FNIII₁₀遵循一条一致的转变途径，其中间状态的特征是A和Gβ链分离。我们测定了FNIII₁₀的折叠自由能和所有与力相关的转变速率，发现从天然状态到中间状态以及从中间状态到解折叠状态的解折叠速率均偏离贝尔模型。我们构建了一个具有明确陷阱和势垒的定量自由能景观，其呈现出分层对称模式。我们的研究结果为FNIII₁₀的构象动力学提供了全面理解，并展示了如何精确绘制多态生物分子的自由能景观，阐明了蛋白质折叠中热稳定性、中间状态和折叠速率之间的关系。
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