Simulations of the Ribosome Suggest Reversible Transitions and Parallel Pathways are Involved in the Large-Scale Functional Motions of tRNA During Translation

Through model building and large-scale computer simulations, we present a structural framework for understanding the molecular mechanisms of transfer RNA (tRNA) motion through the ribosome. In the context of tRNA accommodation (the process by which tRNA enters the ribosomal complex), these models predict that highly-specific functional motions are determined by the atomic details of the ribosome. Significant findings include 1) large-scale reversible fluctuations in tRNA position precede complete tRNA accommodation, 2) the accommodation process possesses multiple kinetic intermediates that may be related to ribosomal “proofreading” and 3) parallel pathways of accommodation may allow incoming tRNA molecules to be re-routed in response to changes in cellular conditions. In addition to illuminating the role of the ribosome's structure, this work also predicts that large changes in entropy in the individual tRNA molecules lead to energetically favorable accommodation pathways. The dynamics predicted in these models are validated through comparison with crystallographic data, explicit-solvent simulations and smFRET experiments.