Abstract
Protein synthesis by the ribosome is coordinated by an intricate series of large-scale conformational rearrangements. Structural studies can provide information about long-lived states, however biological kinetics are controlled by the intervening free-energy barriers. While there has been progress describing the energy landscapes of bacterial ribosomes, very little is known about the energetics of large-scale rearrangements in eukaryotic systems. To address this topic, we constructed an all-atom model with simplified energetics and performed simulations of subunit rotation in the yeast ribosome. In these simulations, the small subunit (SSU; ~1MDa) undergoes spontaneous and reversible rotations (~8°). By enabling the simulation of this rearrangement under equilibrium conditions, these calculations provide initial insights into the molecular factors that control dynamics in eukaryotic ribosomes. Through this, we are able to identify specific inter-subunit interactions that have a pronounced influence on the rate-limiting free-energy barrier. We also show that, as a result of changes in molecular flexibility, the thermodynamic balance between the rotated and unrotated states is temperature-dependent. This effect may be interpreted in terms of differential molecular flexibility within the rotated and unrotated states. Together, these calculations provide a foundation, upon which the field may begin to dissect the energetics of these complex molecular machines.
Highlights
The ribosome is a massive molecular assembly that undergoes a wide range conformational rearrangements in order to accurately synthesize proteins [1,2,3,4]
To study the dynamics of subunit rotation for a eukaryotic ribosome, we applied molecular dynamics simulations with an all-atom model (206,389 atoms) that employs a simplified energetic representation
We extend to an all-atom representation, such that the presented model may later be used to study the precise influence of sterics during tRNA rearrangements in the ribosome
Summary
The ribosome is a massive molecular assembly that undergoes a wide range conformational rearrangements in order to accurately synthesize proteins [1,2,3,4]. The overall architecture of the ribosome is commonly described in terms of the large subunit (LSU) and small subunit (SSU), where each has three distinct tRNA binding sites (Figure 1). Aminoacyl-transfer RNA (aa-tRNA) molecules must decode messenger RNA (mRNA). Upon recognition of an mRNA codon, the incoming aa-tRNA molecule binds the ribosomal A site. After peptide bond formation, the A-site and P-site tRNA molecules are displaced to the P and E sites, respectively. This process, called translocation, leads to a vacant A site, which allows the ribosome to decode the mRNA codon
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