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Ribosome Mechanics Informs About Mechanism Biochemistry, Biophysics and Molecular Biology Publications Biochemistry, Biophysics and Molecular Biology 2-27-2016 Ribosome Mechanics Informs about Mechanism Michael T. Zimmermann Iowa State University Kejue Jia Iowa State University, [email protected] Robert L. Jernigan Iowa State University, [email protected] Follow this and additional works at: https://lib.dr.iastate.edu/bbmb_ag_pubs Part of the Genetics Commons, and the Molecular Biology Commons The complete bibliographic information for this item can be found at https://lib.dr.iastate.edu/ bbmb_ag_pubs/296. For information on how to cite this item, please visit http://lib.dr.iastate.edu/howtocite.html. This Article is brought to you for free and open access by the Biochemistry, Biophysics and Molecular Biology at Iowa State University Digital Repository. It has been accepted for inclusion in Biochemistry, Biophysics and Molecular Biology Publications by an authorized administrator of Iowa State University Digital Repository. For more information, please contact [email protected]. Ribosome Mechanics Informs about Mechanism Abstract The essential aspects of the ribosome’s mechanism can be extracted from coarse-grained simulations, including the ratchet motion, the movement together of critical bases at the decoding center, as well as movements of the peptide tunnel lining that assist in the expulsion of the synthesized peptide. Because of its large size, coarse-graining helps to simplify and to aid in the understanding of its mechanism. Results presented here utilize coarse-grained elastic network modeling to extract the dynamics, and both RNAs and proteins are coarse-grained. We review our previous results, showing the well-known ratchet motions and the motions in the peptide tunnel and in the mRNA tunnel. The motions of the lining of the peptide tunnel appear to assist in the expulsion of the growing peptide chain, and clamps at the ends of the mRNA tunnel with three proteins, ensure that the mRNA is held tightly during decoding and essential for the helicase activity at the entrance. The entry clamp may also assist in base recognition to ensure proper selection of the incoming tRNA. The overall precision with which the ribosome operates as a machine is remarkable. Keywords ribosome mechanism, dynamics simulations, RNA mechanics, mRNA Disciplines Biochemistry, Biophysics, and Structural Biology | Genetics | Molecular Biology Comments This is a manuscript of an article published as Zimmermann, Michael T., Kejue Jia, and Robert L. Jernigan. "Ribosome mechanics informs about mechanism." Journal of molecular biology 428, no. 5 (2016): 802-810. doi:10.1016/j.jmb.2015.12.003. Posted with permission. Creative Commons License This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License. This article is available at Iowa State University Digital Repository: https://lib.dr.iastate.edu/bbmb_ag_pubs/296 HHS Public Access Author manuscript Author Manuscript Author ManuscriptJ Mol Biol Author Manuscript. Author manuscript; Author Manuscript available in PMC 2017 February 27. Published in final edited form as: J Mol Biol. 2016 February 27; 428(5 Pt A): 802–810. doi:10.1016/j.jmb.2015.12.003. Ribosome Mechanics Informs about Mechanism MICHAEL T. ZIMMERMANN*, Jernigan Laboratory, Iowa State University, Ames, IA 50011 USA KEJUE JIA, and Jernigan Laboratory, Iowa State University, Ames, IA 50011 USA ROBERT L. JERNIGAN Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, IA 50011 USA MICHAEL T. ZIMMERMANN: [email protected]; KEJUE JIA: [email protected]; ROBERT L. JERNIGAN: [email protected] Abstract The essential aspects of the ribosome’s mechanism can be extracted from coarse-grained simulations, including the ratchet motion, the movement together of critical bases at the decoding center, as well as movements of the peptide tunnel lining that assist in the expulsion of the synthesized peptide. Because of its large size, coarse-graining helps to simplify and to aid in the understanding of its mechanism. Results presented here utilize coarse-grained elastic network modeling to extract the dynamics, and both RNAs and proteins are coarse-grained. We review our previous results, showing the well-known ratchet motions and the motions in the peptide tunnel and in the mRNA tunnel. The motions of the lining of the peptide tunnel appear to assist in the expulsion of the growing peptide chain, and clamps at the ends of the mRNA tunnel with three proteins, ensure that the mRNA is held tightly during decoding and essential for the helicase activity at the entrance. The entry clamp may also assist in base recognition to ensure proper selection of the incoming tRNA. The overall precision with which the ribosome operates as a machine is remarkable. Graphical Abstract *Present Address: Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN 55905 Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. ZIMMERMANN et al. Page 2 Author Manuscript Author Manuscript Author Manuscript Author Manuscript Keywords ribosome mechanism; dynamics simulations; RNA mechanics; mRNA Introduction Translation of the DNA genetic information into protein products is the essential process carried out by the ribosome. The ribosome is a remarkable intricate ribonucleo-protein machine, which interacts with a set of diverse substrates and co-factors during the process of translation. Understanding the ribosome’s dynamics is essential for comprehending its mechanism. Much effort has gone into identifying the structural components of the ribosome in its different forms, the structures of the ribosomes of diverse organisms, and identifying where drugs bind. All of these studies lead to a viewpoint that the ribosome is a highly robust molecular machine with many moving parts. Indeed, the number of distinct functional ribosomal conformations (states) required during translation is unknown and may remain incompletely characterized by experiments despite the ribosome’s importance for the viability of cells. Computations can play a role by discovering additional states. There have been many attempts to develop more detailed understanding of the mechanisms of the ribosome’s function. Cryo-electron microscopy (cryo-EM) has provided much of our understanding of the steps involved in protein synthesis [1–6]. From an analysis of 3-D cryo-EM snapshots of the intact ribosome in its various functional states, Frank and Agrawal [3] reported ratchet-like rotations of the 30S subunit relative to the 50S subunit during translocation, which closely resembles the motions observed in our dynamics simulations (Fig. 1) [7]. Many details have been understood regarding the sequential steps during translocation, but all details have not yet been fully developed [8, 9]. Other methods such as NMR and FRET are providing additional details [10–18]. Experimental structural determination can provide the structures of multiple states of ribosomal protein and RNA components, corresponding to many different conditions with different ligands bound, immobilized in various ways, in different environments, etc., but structure determination of all possible structural states to map out all details of the ribosome’s mechanism is overall a daunting task. Computations can play a critical important in supplementing the available structural and functional information with simulations providing further details of the ribosome’s dynamics. A complete understanding of the mechanism will only be fully realized if we collect information about its dynamics from a variety of different J Mol Biol. Author manuscript; available in PMC 2017 February 27. ZIMMERMANN et al. Page 3 computational simulations. The motions of the ribosome are being sampled successfully for Author Manuscript Author Manuscript Author Manuscript Author Manuscript extremely long times with atomic molecular dynamics simulations by the group of Sanbonmatsu. Such simulations do not always, however, yield simple descriptions of the mechanism. Different aspects of the dynamics of the ribosome and its constituents have been investigated using various computational approaches such as full-atomic molecular dynamics [19–27], coarse-grained molecular dynamics [28], normal mode analysis using a coarse-grained potential [7, 18, 29–32], elastic network models [33, 34] and combining experimental observations with computational methods [35]. We focus here on the mechanical behavior of the ribosome in a coarse-grained approach. Our use of simple elastic network models is an appropriate and informative tool for this purpose that can provide simple results to permit the comprehension of many mechanistic details of translation and protein elongation. More thorough investigations of a variety of models with various components included or excluded is important for understanding ribosomal functioning. Such simulations can complement and enhance what can be learned experimentally. Exploring the dynamics of biological systems is key for understanding the ribosome’s functional mechanisms.
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