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The ribosome lowers the entropic penalty of protein folding.

ABSTRACT: Most proteins fold during biosynthesis on the ribosome¹, and co-translational folding energetics, pathways and outcomes of many proteins have been found to differ considerably from those in refolding studies^2-10. The origin of this folding modulation by the ribosome has remained unknown. Here we have determined atomistic structures of the unfolded state of a model protein on and off the ribosome, which reveal that the ribosome structurally expands the unfolded nascent chain and increases its solvation, resulting in its entropic destabilization relative to the peptide chain in isolation. Quantitative ¹⁹F NMR experiments confirm that this destabilization reduces the entropic penalty of folding by up to 30 kcal mol^-1 and promotes formation of partially folded intermediates on the ribosome, an observation that extends to other protein domains and is obligate for some proteins to acquire their active conformation. The thermodynamic effects also contribute to the ribosome protecting the nascent chain from mutation-induced unfolding, which suggests a crucial role of the ribosome in supporting protein evolution. By correlating nascent chain structure and dynamics to their folding energetics and post-translational outcomes, our findings establish the physical basis of the distinct thermodynamics of co-translational protein folding.

SUBMITTER: Streit JO

PROVIDER: S-EPMC11374706 | biostudies-literature | 2024 Sep

REPOSITORIES: biostudies-literature

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The ribosome lowers the entropic penalty of protein folding.

Streit Julian O JO Bukvin Ivana V IV Chan Sammy H S SHS Bashir Shahzad S Woodburn Lauren F LF Włodarski Tomasz T Figueiredo Angelo Miguel AM Jurkeviciute Gabija G Sidhu Haneesh K HK Hornby Charity R CR Waudby Christopher A CA Cabrita Lisa D LD Cassaignau Anaïs M E AME Christodoulou John J

Nature 20240807 8028

Most proteins fold during biosynthesis on the ribosome<sup>1</sup>, and co-translational folding energetics, pathways and outcomes of many proteins have been found to differ considerably from those in refolding studies<sup>2-10</sup>. The origin of this folding modulation by the ribosome has remained unknown. Here we have determined atomistic structures of the unfolded state of a model protein on and off the ribosome, which reveal that the ribosome structurally expands the unfolded nascent chain ...[more]

PMID: 39112704

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Project description:Although molecular simulation methods have yielded valuable insights into mechanistic aspects of protein refolding in vitro, they have up to now not been used to model the folding of proteins as they are actually synthesized by the ribosome. To address this issue, we report here simulation studies of three model proteins: chymotrypsin inhibitor 2 (CI2), barnase, and Semliki forest virus protein (SFVP), and directly compare their folding during ribosome-mediated synthesis with their refolding from random, denatured conformations. To calibrate the methodology, simulations are first compared with in vitro data on the folding stabilities of N-terminal fragments of CI2 and barnase; the simulations reproduce the fact that both the stability and thermal folding cooperativity increase as fragments increase in length. Coupled simulations of synthesis and folding for the same two proteins are then described, showing that both fold essentially post-translationally, with mechanisms effectively identical to those for refolding. In both cases, confinement of the nascent polypeptide chain within the ribosome tunnel does not appear to promote significant formation of native structure during synthesis; there are however clear indications that the formation of structure within the nascent chain is sensitive to location within the ribosome tunnel, being subject to both gain and loss as the chain lengthens. Interestingly, simulations in which CI2 is artificially stabilized show a pronounced tendency to become trapped within the tunnel in partially folded conformations: non-cooperative folding, therefore, appears in the simulations to exert a detrimental effect on the rate at which fully folded conformations are formed. Finally, simulations of the two-domain protease module of SFVP, which experimentally folds cotranslationally, indicate that for multi-domain proteins, ribosome-mediated folding may follow different pathways from those taken during refolding. Taken together, these studies provide a first step toward developing more realistic methods for simulating protein folding as it occurs in vivo.

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The ribosome lowers the entropic penalty of protein folding.

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The ribosome lowers the entropic penalty of protein folding.

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