How Mechanical Forces on the Ribosome Modulate the Speed of Protein Synthesis
Digital Object Identifier (DOI)
Mechanical forces acting on the ribosome can alter the speed of protein synthesis. These forces can arise from co-translational protein folding, indicating that co-translational processes can regulate translation through mechanochemical mechanisms. The factors governing force generation due to co-translational folding and the contribution of unfolded nascent chain segments to the magnitude of the pulling force are unknown. Furthermore, the mechanism by which force is transduced 10 nm to the ribosome's catalytic core, and how it modulates peptide bond formation are also unknown. Here, we address these issues using all-atom and coarse-grained molecular dynamics simulations as well as in situ experimental measurements of changes in nascent-chain extension in the exit tunnel. We first show that domain topology and stability play a key role in determining the magnitude of the pulling force generated during co-translational folding. Next, 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 is transmitted through the polypeptide backbone to the ribosome's catalytic core. Utilizing quantum mechanical calculations, we find that these pulling forces decrease the free energy barrier height to peptide bond formation indicating that elongating chains can accelerate translation. Since nascent protein segments start out as unfolded structural ensembles, these results indicate a universal pulling force is present during protein synthesis that increases as a protein elongates and modulates the speed of synthesis.
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Citation / Publisher Attribution
Biophysical Journal, v. 114, issue 3, supp. 1, p. 593A
Scholar Commons Citation
Fritch, Benjamin; Leininger, Sarah; Hudson, Phillip S.; Woodcock, H. Lee III; Deutsch, Carol; and O'Brien, Edward P., "How Mechanical Forces on the Ribosome Modulate the Speed of Protein Synthesis" (2018). Chemistry Faculty Publications. 91.