 Molecular Simulations of Cotranslational Protein Folding: Fragment Stabilities, Folding Cooperativity, and Trapping in the RibosomeAdrian H Elcock PLOS Computational Biology, 2006, vol. 2, issue 7, 1-18 Abstract: 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.Synopsis: The question of how proteins fold into their three-dimensional native conformations continues to be a subject of considerable interest, in large part because misfolding or aggregation of proteins is associated with a number of important diseases. Most previous research has focused on how proteins refold from denatured conformations in vitro, and much of the experimentally observed behavior has proven to be explicable with molecular simulations performed on computers. Recently attention has begun to move toward understanding protein folding as it occurs in vivo, which development requires, among other things, consideration of potential interactions with chaperonins and non-specific crowding effects due to the high macromolecular concentrations encountered in physiological conditions. Also under increasing consideration experimentally is the possibility that proteins might begin to fold while being synthesized (i.e., cotranslational folding), and the purpose of this work is therefore to develop and apply a first molecular simulation strategy capable of modeling this process. The simulations thus described, while not free of assumptions and approximations, nevertheless provide some intriguing glimpses into how the process of protein folding might be modulated through coupling to synthesis within the large ribosomal subunit. Date: 2006 Downloads: (external link) Related works: Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text Persistent link: https://EconPapers.repec.org/RePEc:plo:pcbi00:0020098 DOI: 10.1371/journal.pcbi.0020098 Access Statistics for this article More articles in PLOS Computational Biology from Public Library of Science |
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