Modeling the effect of codon translation rates on co-translational protein folding mechanisms of arbitrary complexity

Caniparoli, Luca; O’Brien, Edward P.

doi:10.1063/1.4916914

Cited by 6 publications

(13 citation statements)

References 45 publications

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“…To overcome the limited sampling of the all-atom simulations, which led to imprecise force estimates, we turned to coarse-grained simulations to determine a precise magnitude of the pulling force associated with increased nascent-chain length. We employed a coarse-grained model of RNCs that has been developed and extensively applied over the past several years. − This coarse-grained model allows tens of microseconds to be simulated, and the smoothed energy landscape and low-friction Langevin Dynamics results in a million-fold acceleration of dynamics . Thus, individual trajectories correspond to tens of seconds of experimental time.…”

Section: Resultsmentioning

confidence: 99%

Origins of the Mechanochemical Coupling of Peptide Bond Formation to Protein Synthesis

et al. 2018

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Mechanical forces acting on the ribosome can alter the speed of protein synthesis, indicating that mechanochemistry can contribute to translation control of gene expression. The naturally occurring sources of these mechanical forces, the mechanism by which they are transmitted 10 nm to the ribosome's catalytic core, and how they influence peptide bond formation rates are largely unknown. Here, we identify a new source of mechanical force acting on the ribosome by using in situ experimental measurements of changes in nascent-chain extension in the exit tunnel in conjunction with all-atom and coarse-grained computer simulations. We demonstrate that when the number of residues composing a nascent chain increases, its unstructured segments outside the ribosome exit tunnel generate piconewtons of force that are fully transmitted to the ribosome's P-site. The route of force transmission is shown to be through the nascent polypetide's backbone, not through the wall of the ribosome's exit tunnel. Utilizing quantum mechanical calculations we find that a consequence of such a pulling force is to decrease the transition state free energy barrier to peptide bond formation, indicating that the elongation of a nascent chain can accelerate translation. Since nascent protein segments can start out as largely unfolded structural ensembles, these results suggest a pulling force is present during protein synthesis that can modulate translation speed. The mechanism of force transmission we have identified and its consequences for peptide bond formation should be relevant regardless of the source of the pulling force.

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Section: Resultsmentioning

confidence: 99%

Origins of the Mechanochemical Coupling of Peptide Bond Formation to Protein Synthesis

et al. 2018

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“…A coarse-grain representation of the E. coli 50S ribosomal subunit and a dye-modified HemK coarse-grain structure (Figure D) were used in all synthesis simulations. To model domain folding we use a Go̅-based Hamiltonian utilized in previous studies of cotranslational folding. − To model dimensional collapse we use another Hamiltonian that approximates the influence of good-solvent conditions on the HemK NTD. Finally, we use a third Hamiltonian that approximates the influence of poor-solvent conditions with the introduction of nonspecific attractive interactions that cause domain collapse in bulk solution.…”

Section: Resultsmentioning

confidence: 99%

“…Here, we present results from coarse-grained, low-friction Langevin dynamics simulations of HemK synthesis that were performed with three different Hamiltonians to assess which driving force yields a compaction process that is most consistent with the experimental data. The first Hamiltonian, which models domain folding, is a Go̅-based model previously used to model cotranslational folding in silico. − The second Hamiltonian approximates the influence of a good solvent on the nascent protein to model dimensional collapse. The third Hamiltonian models the influence of a poor solvent to permit nonspecific collapse.…”

Section: Introductionmentioning

confidence: 99%

Structural Origins of FRET-Observed Nascent Chain Compaction on the Ribosome

Nissley

O’Brien

2018

J. Phys. Chem. B

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A fluorescence signal arising from a Förster resonance energy transfer process was used to monitor conformational changes of a domain within the E. coli protein HemK during its synthesis by the ribosome. An increase in fluorescence was observed to begin 10 s after translation was initiated, indicating the domain became more compact in size. Since fluorescence only reports a single value at each time point it contains very little information about the structural ensemble that gives rise to it. Here, we supplement this experimental information with coarse-grained simulations that describe protein conformations and transitions at a spatial resolution of 3.8 Å. We use these simulations to test three hypotheses that might explain the cause of domain compaction: (1) that poor solvent quality conditions drive the unfolded state to compact, (2) that a change in the dimension of the space the domain occupies upon moving outside the exit tunnel causes compaction, or (3) that domain folding causes compaction. We find that domain folding and dimensional collapse are both consistent with the experimental data, while poor-solvent collapse is inconsistent. We identify alternative dye labeling positions on HemK that upon fluorescence can differentiate between the domain folding and dimensional collapse mechanisms. Partial folding of domains has been observed in C-terminally truncated forms of proteins. Therefore, it is likely that the experimentally observed compact state is a partially folded intermediate consisting, according to our simulations, of the first three helices of the HemK N-terminal domain adopting a native, tertiary configuration. With these simulations we also identify the possible cotranslational folding pathways of HemK.

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“…To test the accuracy of predictions from the master equation (eq 3), we used previously generated 20 coarse-grained simulation data of the synthesis of the single-domain MIT protein. MIT is a 77-residue protein that forms a 3-helix bundle in its folded state and can populate unfolded, intermediate, and folded states (Figure 2c).…”

Section: ■ Resultsmentioning

confidence: 99%

“…Markov state definitions that have been previously published. 20 Specifically, we used two order parameters, the fraction of native contacts between helices 1 and 2 (Q 1−2 ) and between helix 3 and helices 1 and 2 (Q 12−3 ). retain their constant values, and it is only the n 12 and n 12−3 terms which will decrease compared to the fully synthesized MIT situation.…”

Section: ∑ ∑mentioning

confidence: 99%

Physical Origins of Codon Positions That Strongly Influence Cotranslational Folding: A Framework for Controlling Nascent-Protein Folding

2016

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An emerging paradigm in the field of in vivo protein biophysics is that nascent-protein behavior is a type of nonequilibrium phenomenon, where translation-elongation kinetics can be more important in determining nascent-protein behavior than the thermodynamic properties of the protein. Synonymous codon substitutions, which change the translation rate at select codon positions along a transcript, have been shown to alter cotranslational protein folding, suggesting that evolution may have shaped synonymous codon usage in the genomes of organisms in part to increase the amount of folded and functional nascent protein. Here, we develop a Monte Carlo-master-equation method that allows for the control of nascent-chain folding during translation through the rational design of mRNA sequences to guide the cotranslational folding process. We test this framework using coarse-grained molecular dynamics simulations and find it provides optimal mRNA sequences to control the simulated, cotranslational folding of a protein in a user-prescribed manner. With this approach we discover that some codon positions in a transcript can have a much greater impact on nascent-protein folding than others because they tend to be positions where the nascent chain populates states that are far from equilibrium, as well as being dependent on a complex ratio of time scales. As a consequence, different cotranslational profiles of the same protein can have different critical codon positions and different numbers of synonymous mRNA sequences that encode for them. These findings explain that there is a fundamental connection between the nonequilibrium nature of cotranslational processes, nascent-protein behavior, and synonymous codon usage.

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Modeling the effect of codon translation rates on co-translational protein folding mechanisms of arbitrary complexity

Cited by 6 publications

References 45 publications

Origins of the Mechanochemical Coupling of Peptide Bond Formation to Protein Synthesis

Origins of the Mechanochemical Coupling of Peptide Bond Formation to Protein Synthesis

Structural Origins of FRET-Observed Nascent Chain Compaction on the Ribosome

Physical Origins of Codon Positions That Strongly Influence Cotranslational Folding: A Framework for Controlling Nascent-Protein Folding

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