Non-ergodicity of a globular protein extending beyond its functional timescale

Release date:2022-08-21 Page views:716


Recently, Chemical Science, the flagship journal of the Royal Society of Chemistry, published a new edge research article entitled as “Non-ergodicity of a globular protein extending beyond its functional timescale” by Prof. Liang Hong’s group (Institute of Natural Sciences & School of physics and astronomy & Zhangjiang Institute for Advanced Study), which reported the non-ergodic protein internal dynamics that the functional dynamics in a multi-domain protein slows down with increasing the observational time and it exhibits a large degree of heterogeneity among individual protein molecules. 

Protein internal dynamics is crucial for its function. How these motions on different timescales relate to and influence each other, and how the overall characteristics of internal dynamics relate to biological function is of particular interest in biophysics. Also, the intriguing possibility exists that otherwise identical single protein molecules might be physically distinct on timescales approaching their functional times (e.g., enzyme catalytic rates). In this regard, a particularly interesting question is whether internal protein dynamics is ergodic, i.e., time-averaged observables are equal to its ensemble average.

The group performed numerous single-molecule fluorescence resonance energy transfer (smFRET) experiments and molecular dynamics (MD) simulations to study the internal dynamics of a multi-domain protein, SHP2. The results demonstrate that functional inter-domain motions in the protein show heterogeneity and non-ergodicity over wide time windows: from 10-12 to 10s. Moreover, we observed striking aging behavior, i.e., the effective internal flexibility of the protein decrease with observation time. Furthermore, as illustrated by control simulations and experiments on a single-strand DNA (ssDNA)of similar size, which behaves ergodically with an energy landscape resembling a one-dimensional linear chain. We demonstrate  that the anomalous dynamics of the protein arise from the characteristic protein energy landscape, which has a much higher dimensionality that that of the ssDNA, unique hierarchical structure, and “chained-islands” topology. The present findings significantly recast existing ideas in molecular biophysics connecting ensemble-averaged protein dynamics to biological function. Instead, non-ergodicity splits the population of otherwise identical proteins into subpopulations with drastically distinct conformations, flexibilities, and reaction rates over timescales longer than needed for the biological function. 

The first author of this article is Ph.D. student Jun Li from Prof. Liang Hong’s group, and Prof. Liang Hong from the Institute of Natural Sciences and School of Physics and Astronomy is the corresponding author. The theoretical model was developed with the help of Prof. Jeremy C. Smith from the University of Tennessee and Oak Ridge National Laboratory (USA), and Dr. Aljaž Godec from Max Planck Institute for Biophysical Chemistry (Germany). The single-molecule experiments were carried out with the help of Dr. JingFei Xie, Associate Prof. Cong Liu in the Chinese Academy of Sciences (China), and Prof. Keith R. Weninger from North Carolina State University (USA). The work was supported by the National Natural Science Foundation of China, Student Innovation Center, and Center for High-Performance Computing at SJTU.

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