Cotranslational protein folding can promote the formation of correct folding intermediate

Xiao, Y.; Tao, P.

doi:10.1101/2020.05.08.084228

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bioRxiv · 10.1101/2020.05.08.084228

Cotranslational protein folding can promote the formation of correct folding intermediate

Xiao, Y.·Tao, P.

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Abstract

Cotranslational folding is vital for proteins to form correct structures in vivo. However, it is still unclear how a nascent chain folds at atomic resolution during the translation process. Previously, we have built a model of ribosomal exit tunnel and investigated cotranslational folding of a three-helices protein by using all-atom molecular dynamics simulations. Here we shall study the cotranslational folding of three mainly-{beta} proteins using the same method and find that cotranslational folding can enhance helical population in most cases and reduce nonnative long-range contacts before emerging from the ribosomal exit tunnel. After exiting the tunnel, all proteins fall into local minimal states and structural ensembles in cotranslational folding are more helical than in free folding. Importantly, for GTT WW domain, one local minimal state in cotranslational folding is known as correct folding intermediate, which is not found in free folding. This result suggests that cotranslational folding may directly increase folding efficiency by accelerating sampling more than by avoiding the misfolded state, which is a mainstream viewpoint in present. In addition, our method can serve as a general scheme to study cotranslational folding process of proteins. Statement of SignificanceIn cell, the formations of correct three-dimensional structures of proteins, namely protein folding, are essential to human health. Misfolding can lead to serious diseases such as Alzheimers disease and mad cow disease. As the first step of in vivo folding, the effect of cotranslational folding on the correct folding of proteins has been the focus of scientific research in this century. Although some experiments have shown that cotranslational folding can improve the efficiency of folding, its microscopic mechanism is not yet clear. In this paper, we study the process of cotranslational folding of three proteins by using all-atom molecular dynamics simulations, and try to reveal some aspects of the mechanism of cotranslational folding from a microscopic perspective.

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Xiao, Y., Tao, P.. 2020-05-10. Cotranslational protein folding can promote the formation of correct folding intermediate. https://doi.org/10.1101/2020.05.08.084228

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