Computational evidence that fast translation speed can increase the probability of cotranslational protein folding

Wang, Ercheng; Wang, Jun; Chen, Changjun; Xiao, Yi

doi:10.1038/srep15316

Cited by 16 publications

(11 citation statements)

References 41 publications

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“…Kinetic modeling predicted that increasing the polypeptide elongation speed can promote cotranslational folding by reducing the number of misfolding events during the time that the ribosome dwells in the misfoldingprone nascent-chain length regime, contrary to the common view that slow synthesis favors native structure formation (31). Consistent with this hypothesis, recent experiments (32,33) and the qualitative trends observed in atomistic molecular dynamics simulations of a small protein (28) imply that slow-translating codons are not always beneficial for cotranslational folding and can promote protein aggregation.…”

Section: Introductionmentioning

confidence: 77%

“…The relationship between elongation rates and cotranslational events is beginning to be quantitatively understood through theoretical, computational and experimental efforts (16,20,(25)(26)(27)(28)(29)(30). Kinetic modeling predicted that increasing the polypeptide elongation speed can promote cotranslational folding by reducing the number of misfolding events during the time that the ribosome dwells in the misfoldingprone nascent-chain length regime, contrary to the common view that slow synthesis favors native structure formation (31).…”

Section: Introductionmentioning

confidence: 99%

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

Trovato

O’Brien

2017

Biophysical Journal

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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 segments increases the fraction of folded proteins by kinetically partitioning more molecules through on-pathway intermediates, decreasing the likelihood of sampling misfolded conformations. Novel to this study, to our knowledge, we observe that differences in protein dynamics, arising from different translation-elongation schedules, can persist long after the nascent protein has been released from the ribosome, and that a sufficient level of energetic frustration is needed for fast-translating codons to be beneficial for folding. These results provide further evidence that fast-translating codons can be as biologically important as pause sites in coordinating cotranslational folding.

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Section: Introductionmentioning

confidence: 77%

Section: Introductionmentioning

confidence: 99%

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

Trovato

O’Brien

2017

Biophysical Journal

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“…There is evidence of computational analysis that fast translation speed can increase the probability of cotranslational protein folding. [75][76][77] It is now important to consider the coding sequence while performing protein folding in silico. In this regard, the recently developed CSandS database is worth to consider while designing protein three-dimensional structure.…”

Section: Translation Kinetics Guides Cotranslational Protein Foldingmentioning

confidence: 99%

Synonymous codons influencing gene expression in organisms

Mitra¹,

Ray²,

Banerjee³

2016

RRBC

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Nowadays, it is beyond doubt that synonymous codons are not the same with respect to expression of a gene. In favor of this, ribosome profiling experiments in vivo and in vitro have suggested that ribosome occupancy time is not the same for different synonymous codons. Therefore, synonymous codons influence differently the speed of translation elongation, which guides further cotranslational folding kinetics of a protein. It is now realized that the position of each codon in a coding sequence is important. The effect of synonymous codons on protein structure is an exciting field of research nowadays. This review discusses the recent developments in this field.

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“…A cellular model should also include non-equilibrium processes, for their importance in regulating protein stability (Samiotakis et al 2009;Gershenson and Gierasch 2011;Wang et al 2015;Bui and Hoang 2016;Gorensek-Benitez et al 2017). Toward this goal, recent simulations of cotranslational folding showed that translation rates may affect the structure and stability of misfolding-prone proteins (Trovato and O'Brien 2017), as well as of multidomain proteins (Tanaka et al 2015).…”

Section: Toward Realistic Molecular Simulations Of Cellular Eventsmentioning

confidence: 99%

Molecular simulations of cellular processes

Trovato

Fumagalli

2017

Biophys Rev

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It is, nowadays, possible to simulate biological processes in conditions that mimic the different cellular compartments. Several groups have performed these calculations using molecular models that vary in performance and accuracy. In many cases, the atomistic degrees of freedom have been eliminated, sacrificing both structural complexity and chemical specificity to be able to explore slow processes. In this review, we will discuss the insights gained from computer simulations on macromolecule diffusion, nuclear body formation, and processes involving the genetic material inside cell-mimicking spaces. We will also discuss the challenges to generate new models suitable for the simulations of biological processes on a cell scale and for cellcycle-long times, including non-equilibrium events such as the co-translational folding, misfolding, and aggregation of proteins. A prominent role will be played by the wise choice of the structural simplifications and, simultaneously, of a relatively complex energetic description. These challenging tasks will rely on the integration of experimental and computational methods, achieved through the application of efficient algorithms.

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Computational evidence that fast translation speed can increase the probability of cotranslational protein folding

Cited by 16 publications

References 41 publications

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

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

Synonymous codons influencing gene expression in organisms

Molecular simulations of cellular processes

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