Non-ergodicity of a globular protein extending beyond its functional timescale. Issue 33 (9th August 2022)

• Record Type: Journal Article
• Authors: Li, Jun; Xie, JingFei; Godec, Aljaž; Weninger, Keith R.; Liu, Cong; Smith, Jeremy C.; Hong, Liang
• Is Part Of: Chemical science. Volume 13:Issue 33(2022)
• Page Start: 9668
• Page End: 9677
• Publication Date: 2022-08-09
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/d2sc03069a
• Languages: English
• ISSNs: 2041-6520

Abstract

Abstract : Internal motions of folded proteins have been assumed to be ergodic, i.e., that the dynamics of a single protein molecule averaged over a very long time resembles that of an ensemble. Abstract : Internal motions of folded proteins have been assumed to be ergodic, i.e., 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 −12 to 10 −7 s and 10 −1 to 10 2 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.