Thermodynamics of co-translational folding and ribosome–nascent chain interactions

Waudby, Christopher A.; Burridge, Charles; Cabrita, Lisa D.; Christodoulou, John

doi:10.1016/j.sbi.2022.102357

Cited by 10 publications

(2 citation statements)

References 67 publications

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“… 51 − 53 In this study, we aimed to investigate the influence of the ribosome on protein folding alone. While it is commonly believed that the ribosome is generally effective in assisting protein folding to native conformations, 14 , 15 , 54 , 55 our data do not consistently support this assumption. We do find the ribosome increases the folding efficiency of DHFR, in which two domains ABD and DLD fold independently.…”

Section: Discussioncontrasting

confidence: 98%

Is Posttranslational Folding More Efficient Than Refolding from a Denatured State: A Computational Study

Nissley

Jiang

et al. 2023

J. Phys. Chem. B

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The folding of proteins into their native conformation is a complex process that has been extensively studied over the past half-century. The ribosome, the molecular machine responsible for protein synthesis, is known to interact with nascent proteins, adding further complexity to the protein folding landscape. Consequently, it is unclear whether the folding pathways of proteins are conserved on and off the ribosome. The main question remains: to what extent does the ribosome help proteins fold? To address this question, we used coarse-grained molecular dynamics simulations to compare the mechanisms by which the proteins dihydrofolate reductase, type III chloramphenicol acetyltransferase, and D-alanine−D-alanine ligase B fold during and after vectorial synthesis on the ribosome to folding from the full-length unfolded state in bulk solution. Our results reveal that the influence of the ribosome on protein folding mechanisms varies depending on the size and complexity of the protein. Specifically, for a small protein with a simple fold, the ribosome facilitates efficient folding by helping the nascent protein avoid misfolded conformations. However, for larger and more complex proteins, the ribosome does not promote folding and may contribute to the formation of intermediate misfolded states cotranslationally. These misfolded states persist posttranslationally and do not convert to the native state during the 6 μs runtime of our coarse-grain simulations. Overall, our study highlights the complex interplay between the ribosome and protein folding and provides insight into the mechanisms of protein folding on and off the ribosome.

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Section: Discussioncontrasting

confidence: 98%

Is Posttranslational Folding More Efficient Than Refolding from a Denatured State: A Computational Study

Nissley

Jiang

et al. 2023

J. Phys. Chem. B

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“…The FLN5-6 nascent chain sequence also consists of the 31 amino-acid linker comprising the fragment of the subsequent filamin domain (FLN6) and the SecM stalling sequence 77 . The FLN5 is the fifth filamin domain (residues 646-750) of the Dictyostelium discoideum gelation factor, and its co-translational folding has been extensively studied through a combination of experimental and computational techniques 66,67,78,79 . For our study, we generated a starting ensemble by randomly selecting 100 conformations of the NC from the FLN5-6 structural ensemble obtained from the previous all-atom structure-based MD simulation 50 ( Fig.…”

Section: Discussionmentioning

confidence: 99%

CryoENsemble - a Bayesian approach for reweighting biomolecular structural ensembles using heterogeneous cryo-EM maps

Włodarski,

Streit,

Mitropoulou

et al. 2023

Preprint

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Cryogenic electron microscopy (cryo-EM) has emerged as a central tool for the determination of structures of complex biological molecules. Accurately characterising the dynamics of such systems, however, remains a challenge. To address this, we introduce cryoENsemble, a method that applies Bayesian reweighing to conformational ensembles derived from molecular dynamics simulations to improve their agreement with cryo-EM data and extract dynamics information. We illustrate the use of cryoENsemble to determine the dynamics of the ribosome-bound state of the co-translational chaperone trigger factor (TF). We also show that cryoENsemble can assist with the interpretation of low-resolution, noisy or unaccounted regions of cryo-EM maps. Notably, we are able to link an unaccounted part of the cryo-EM map to the presence of another protein (methionine aminopeptidase, or MetAP), rather than to the dynamics of TF, and model its TF-bound state. Based on these results, cryoENsemble is expected to find use for challenging heterogeneous cryo-EM maps for various biomolecular systems, especially those encompassing dynamic elements.

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How protein fold: Insights from nuclear magnetic resonance spectroscopy

Zhuravelva

2024

Encyclopedia of Condensed Matter Physics

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Thermodynamics of co-translational folding and ribosome–nascent chain interactions

Cited by 10 publications

References 67 publications

Is Posttranslational Folding More Efficient Than Refolding from a Denatured State: A Computational Study

Is Posttranslational Folding More Efficient Than Refolding from a Denatured State: A Computational Study

CryoENsemble - a Bayesian approach for reweighting biomolecular structural ensembles using heterogeneous cryo-EM maps

How protein fold: Insights from nuclear magnetic resonance spectroscopy

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