Li Jun, Xie JingFei, Godec Aljaž, Weninger Keith R, Liu Cong, Smith Jeremy C, Hong Liang
School of Physics and Astronomy, Shanghai Jiao Tong University Shanghai 200240 China.
Interdisciplinary Research Center on Biology and Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences Shanghai 201203 China.
Chem Sci. 2022 Aug 4;13(33):9668-9677. doi: 10.1039/d2sc03069a. eCollection 2022 Aug 24.
Internal motions of folded proteins have been assumed to be ergodic, , that the dynamics of a single protein molecule averaged over a very long time resembles that of an ensemble. Here, by performing single-molecule fluorescence resonance energy transfer (smFRET) experiments and molecular dynamics (MD) simulations of a multi-domain globular protein, cytoplasmic protein-tyrosine phosphatase (SHP2), we demonstrate that the functional inter-domain motion is observationally non-ergodic over the time spans 10 to 10 s and 10 to 10 s. The difference between observational non-ergodicity and simple non-convergence is discussed. In comparison, a single-strand DNA of similar size behaves ergodically with an energy landscape resembling a one-dimensional linear chain. The observed non-ergodicity results from the hierarchical connectivity of the high-dimensional energy landscape of the protein molecule. As the characteristic time for the protein to conduct its dephosphorylation function is ∼10 s, our findings suggest that, due to the non-ergodicity, individual, seemingly identical protein molecules can be dynamically and functionally different.
折叠蛋白质的内部运动被认为是遍历性的，也就是说，单个蛋白质分子在很长时间内的动力学行为类似于一个系综的动力学行为。在这里，通过对一种多结构域球状蛋白——细胞质蛋白酪氨酸磷酸酶（SHP2）进行单分子荧光共振能量转移（smFRET）实验和分子动力学（MD）模拟，我们证明了在10⁻⁶到10⁻³秒以及10⁻³到10⁰秒的时间跨度内，功能性结构域间运动在观测上是非遍历性的。我们讨论了观测非遍历性与简单不收敛之间的差异。相比之下，类似大小的单链DNA表现出遍历性，其能量景观类似于一维线性链。观察到的非遍历性源于蛋白质分子高维能量景观的层次连通性。由于蛋白质进行去磷酸化功能的特征时间约为10⁻³秒，我们的研究结果表明，由于非遍历性，单个看似相同的蛋白质分子在动力学和功能上可能存在差异。
