Abstract
The ribosome is a biomolecular machine that undergoes multiple large-scale structural rearrangements during protein elongation. Here, we focus on a conformational rearrangement during translocation, known as P/E hybrid-state formation. Using a model that explicitly represents all non-hydrogen atoms, we simulated more than 120 spontaneous transitions, where the tRNA molecule is displaced between the P and E sites of the large subunit. In addition to predicting a free-energy landscape that is consistent with previous experimental observations, the simulations reveal how a six-residue gate-like region can limit P/E formation, where sub-angstrom structural perturbations lead to an order-of-magnitude change in kinetics. Thus, this precisely defined set of residues represents a novel target that may be used to control functional dynamics in bacterial ribosomes. This theoretical analysis establishes a direct relationship between ribosome structure and large-scale dynamics, and it suggests how next-generation experiments may precisely dissect the energetics of hybrid formation on the ribosome.
Highlights
The ribosome is a biomolecular machine that undergoes multiple large-scale structural rearrangements during protein elongation
We observed over 120 spontaneous transitions, where the tRNA molecule moves between the P and E sites of the large subunit, while the small subunit maintains a rotated orientation
The tRNA elbow is displaced by ~20 Å, as measured by RFRET
Summary
The ribosome is a biomolecular machine that undergoes multiple large-scale structural rearrangements during protein elongation. In addition to predicting a free-energy landscape that is consistent with previous experimental observations, the simulations reveal how a six-residue gate-like region can limit P/E formation, where sub-angstrom structural perturbations lead to an order-of-magnitude change in kinetics. This precisely defined set of residues represents a novel target that may be used to control functional dynamics in bacterial ribosomes. After initial association with the ribosome, the aa-tRNA fully binds the ribosomal A site, a process known as accommodation[4] This allows a new peptide bond to be formed, after which rotation of the 30S body[5,6] facilitates the adoption of hybrid conformations[7,8,9], where individual tRNAs are displaced between binding sites on the large subunit. In order for translocation to occur, the P-site tRNA molecule must first transiently form a hybrid P/E configuration[6,7], where the anticodon stem loop (ASL)
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