Fast Protein Translation Can Promote Co- and Posttranslational Folding of Misfolding-Prone Proteins

Biophysical Journal
Fabio Trovato, Edward P O'Brien

Abstract

Chemical kinetic modeling has previously been used to predict that fast-translating codons can enhance cotranslational protein folding by helping to avoid misfolded intermediates. Consistent with this prediction, protein aggregation in yeast and worms was observed to increase when translation was globally slowed down, possibly due to increased cotranslational misfolding. Observation of similar behavior in molecular simulations would confirm predictions from the simpler chemical kinetic model and provide a molecular perspective on cotranslational folding, misfolding, and the impact of translation speed on these processes. All-atom simulations cannot reach the timescales relevant to protein synthesis, and most conventional structure-based coarse-grained models do not allow for nonnative structure formation. Here, we introduce a protocol to incorporate misfolding using the functional forms of publicly available force fields. With this model we create two artificial proteins that are capable of undergoing structural transitions between a native and a misfolded conformation and simulate their synthesis by the ribosome. Consistent with the chemical kinetic predictions, we find that rapid synthesis of misfolding-prone nascent-chain se...Continue Reading

Citations

Dec 1, 2017·Biophysics Reviews·Fabio Trovato, Giordano Fumagalli
Apr 18, 2018·Cold Spring Harbor Perspectives in Biology·Marina V Rodnina
Oct 27, 2017·Proceedings of the National Academy of Sciences of the United States of America·William M Jacobs, Eugene I Shakhnovich
Mar 3, 2019·Proceedings of the National Academy of Sciences of the United States of America·Sarah E LeiningerEdward P O'Brien
Aug 2, 2018·Biochemical Society Transactions·Robert Rauscher, Zoya Ignatova
Apr 2, 2020·The Journal of Physical Chemistry Letters·Yonghyun Song, Changbong Hyeon
Feb 18, 2020·Journal of Molecular Biology·Dylan GirodatKarissa Y Sanbonmatsu
Feb 8, 2018·Current Opinion in Structural Biology·Ajeet K Sharma, Edward P O'Brien
Sep 29, 2018·The Journal of Physical Chemistry. B·Daniel A Nissley, Edward P O'Brien

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