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

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 10² 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.

SUBMITTER: Li J

PROVIDER: S-EPMC9400594 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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

Li Jun J Xie JingFei J Godec Aljaž A Weninger Keith R KR Liu Cong C Smith Jeremy C JC Hong Liang L

Chemical science 20220804 33

Internal motions of folded proteins have been assumed to be ergodic, <i>i.e.</i>, 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 ov ...[more]

PMID: 36091909

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Project description:In silico protein target deconvolution is frequently used for mechanism-of-action investigations; however existing protocols usually do not predict compound functional effects, such as activation or inhibition, upon binding to their protein counterparts. This study is hence concerned with including functional effects in target prediction. To this end, we assimilated a bioactivity training set for 332 targets, comprising 817,239 active data points with unknown functional effect (binding data) and 20,761,260 inactive compounds, along with 226,045 activating and 1,032,439 inhibiting data points from functional screens. Chemical space analysis of the data first showed some separation between compound sets (binding and inhibiting compounds were more similar to each other than both binding and activating or activating and inhibiting compounds), providing a rationale for implementing functional prediction models. We employed three different architectures to predict functional response, ranging from simplistic random forest models ('Arch1') to cascaded models which use separate binding and functional effect classification steps ('Arch2' and 'Arch3'), differing in the way training sets were generated. Fivefold stratified cross-validation outlined cascading predictions provides superior precision and recall based on an internal test set. We next prospectively validated the architectures using a temporal set of 153,467 of in-house data points (after a 4-month interim from initial data extraction). Results outlined Arch3 performed with the highest target class averaged precision and recall scores of 71% and 53%, which we attribute to the use of inactive background sets. Distance-based applicability domain (AD) analysis outlined that Arch3 provides superior extrapolation into novel areas of chemical space, and thus based on the results presented here, propose as the most suitable architecture for the functional effect prediction of small molecules. We finally conclude including functional effects could provide vital insight in future studies, to annotate cases of unanticipated functional changeover, as outlined by our CHRM1 case study.

Dataset Information

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

Publications

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

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