A steric gate controls P/E hybrid-state formation of tRNA on the ribosome

Levi, Mariana; Walak, Kelsey N.; Wang, Ailun; Mohanty, Udayan; Whitford, Paul C.

doi:10.1038/s41467-020-19450-0

Cited by 19 publications

(24 citation statements)

References 78 publications

(146 reference statements)

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“…In the current study, 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. This consideration is motivated by previous simulations of bacterial ribosomes, which have demonstrated the critical influence of molecular sterics on tRNA dynamics during accommodation [43], A/P hybrid formation [44], P/E hybrid formation [45] and tRNA translocation [32]. In order for our model to have future utility to address these motions in eukaryotic ribosomes, it is necessary to employ atomic resolution.…”

Section: Simulating Spontaneous Subunit Rotation Events In a Complete Ribosomementioning

confidence: 99%

The Dynamics of Subunit Rotation in a Eukaryotic Ribosome

et al. 2021

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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; ∼1 MDa) undergoes spontaneous and reversible rotation events (∼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.

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Section: Simulating Spontaneous Subunit Rotation Events In a Complete Ribosomementioning

confidence: 99%

The Dynamics of Subunit Rotation in a Eukaryotic Ribosome

et al. 2021

Self Cite

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show abstract

“…In the current study, we extend to an all-atom representation, such that the presented models may later be used to study the precise influence of sterics during tRNA rearrangements in the ribosome. This consideration is motivated by previous simulations of bacterial ribosomes, which have demonstrated the critical influence of molecular sterics on tRNA dynamics during accommodation [39], A/P hybrid formation [40], P/E hybrid formation [41] and tRNA translocation [28]. In order for our model to have future utility to address these motions in eukaryotic ribosomes, it is necessary to employ atomic resolution.…”

Section: Simulating Spontaneous Subunit Rotation Events In a Complete Ribosomementioning

confidence: 99%

The dynamics of subunit rotation in a eukaryotic ribosome

Freitas

Fuchs

Oliveira

et al. 2021

Preprint

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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 ($\sim8^\circ$). 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.

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“…The success of these simplified models to capture folding dynamics is a reflection of the strong limitations that are imposed by molecular sterics and the complexity of folded conformations ( Shea et al, 1999 ; Gosavi et al, 2006 ). Inspired by studies of folding, all-atom variants were later used to simulate rearrangements in large assemblies, such as ribosomes ( Nguyen and Whitford, 2016 ; Levi et al, 2020 ) or viral capsids ( Noel et al, 2016 ; Whitford et al, 2020 ). Despite the simplicity of the models, mechanistic aspects of the dynamics are often robust to the model parameters.…”

Section: Introductionmentioning

confidence: 99%

Sterically confined rearrangements of SARS-CoV-2 Spike protein control cell invasion

Dodero-Rojas

Onuchic

Whitford

2021

eLife

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly contagious, and transmission involves a series of processes that may be targeted by vaccines and therapeutics. During transmission, host cell invasion is controlled by a large-scale (200–300 Å) conformational change of the Spike protein. This conformational rearrangement leads to membrane fusion, which creates transmembrane pores through which the viral genome is passed to the host. During Spike-protein-mediated fusion, the fusion peptides must be released from the core of the protein and associate with the host membrane. While infection relies on this transition between the prefusion and postfusion conformations, there has yet to be a biophysical characterization reported for this rearrangement. That is, structures are available for the endpoints, though the intermediate conformational processes have not been described. Interestingly, the Spike protein possesses many post-translational modifications, in the form of branched glycans that flank the surface of the assembly. With the current lack of data on the pre-to-post transition, the precise role of glycans during cell invasion has also remained unclear. To provide an initial mechanistic description of the pre-to-post rearrangement, an all-atom model with simplified energetics was used to perform thousands of simulations in which the protein transitions between the prefusion and postfusion conformations. These simulations indicate that the steric composition of the glycans can induce a pause during the Spike protein conformational change. We additionally show that this glycan-induced delay provides a critical opportunity for the fusion peptides to capture the host cell. In contrast, in the absence of glycans, the viral particle would likely fail to enter the host. This analysis reveals how the glycosylation state can regulate infectivity, while providing a much-needed structural framework for studying the dynamics of this pervasive pathogen.

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A steric gate controls P/E hybrid-state formation of tRNA on the ribosome

Cited by 19 publications

References 78 publications

The Dynamics of Subunit Rotation in a Eukaryotic Ribosome

The Dynamics of Subunit Rotation in a Eukaryotic Ribosome

The dynamics of subunit rotation in a eukaryotic ribosome

Sterically confined rearrangements of SARS-CoV-2 Spike protein control cell invasion

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