Rotation-Activated and Cooperative Zipping Characterize Class I Viral Fusion Protein Dynamics

Eddy, Nathanial R.; Onuchic, José N.

doi:10.1016/j.bpj.2018.03.005

Cited by 5 publications

(5 citation statements)

References 57 publications

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“…Although structure-based methods lack some of the detail present in explicit solvent MD, they are relatively rapid and offer significantly greater conformational sampling. Structure-based methods have also proven excellent at resolving geometric constraints during conformational change across a diverse range of biological systems, including macromolecular systems such as the ribosome (47,61,62).…”

Section: Ef-tu Changes Conformation Within Ternary Complex Prior To Itsmentioning

confidence: 99%

Elongation factor-Tu can repetitively engage aminoacyl-tRNA within the ribosome during the proofreading stage of tRNA selection

Morse

Girodat

Burnett

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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The substrate for ribosomes actively engaged in protein synthesis is a ternary complex of elongation factor Tu (EF-Tu), aminoacyl-tRNA (aa-tRNA), and GTP. EF-Tu plays a critical role in mRNA decoding by increasing the rate and fidelity of aa-tRNA selection at each mRNA codon. Here, using three-color single-molecule fluorescence resonance energy transfer imaging and molecular dynamics simulations, we examine the timing and role of conformational events that mediate the release of aa-tRNA from EF-Tu and EF-Tu from the ribosome after GTP hydrolysis. Our investigations reveal that conformational changes in EF-Tu coordinate the rate-limiting passage of aa-tRNA through the accommodation corridor en route to the peptidyl transferase center of the large ribosomal subunit. Experiments using distinct inhibitors of the accommodation process further show that aa-tRNA must at least partially transit the accommodation corridor for EF-Tu⋅GDP to release. aa-tRNAs failing to undergo peptide bond formation at the end of accommodation corridor passage after EF-Tu release can be reengaged by EF-Tu⋅GTP from solution, coupled to GTP hydrolysis. These observations suggest that additional rounds of ternary complex formation can occur on the ribosome during proofreading, particularly when peptide bond formation is slow, which may serve to increase both the rate and fidelity of protein synthesis at the expense of GTP hydrolysis.

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Section: Ef-tu Changes Conformation Within Ternary Complex Prior To Itsmentioning

confidence: 99%

Elongation factor-Tu can repetitively engage aminoacyl-tRNA within the ribosome during the proofreading stage of tRNA selection

Morse

Girodat

Burnett

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…The coarse-grained structurebased model, a well-established model, comprehends a novel way to investigate the mechanisms associated with protein folding and function (20-22, 24, 33-38). In the current context of decoding virus entry mechanism, this model successfully characterized Class-I viral fusion protein dynamics including conformational rearrangement of a viral surface glycoprotein, influenza hemagglutinin (HA) during its prefusion and postfusion states (26,39).…”

Section: Super-symmetric Contact Map Generation Methodmentioning

confidence: 99%

Dynamical asymmetry exposes 2019-nCoV prefusion spike

Roy

2020

Preprint

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The novel coronavirus (2019-nCoV) spike protein is a smart molecular machine that instigates the entry of coronavirus to the host cell causing the COVID-19 pandemic. In this study, a structural-topology based model Hamiltonian of C3 symmetric trimeric spike is developed to explore its complete conformational energy landscape using molecular dynamic simulations. The study finds 2019-nCoV to adopt a unique strategy by undertaking a dynamic conformational asymmetry induced by a few unique inter-chain interactions. This results in two prevalent asymmetric structures of spike where one or two spike heads lifted up undergoing a dynamic transition likely to enhance rapid recognition of the host-cell receptor turning on its high-infectivity. The crucial interactions identified in this study are anticipated to potentially affect the efficacy of therapeutic targets.One Sentence Summary: Inter-chain-interaction driven rapid symmetry breaking strategy adopted by the prefusion trimeric spike protein likely to make 2019-nCoV highly infective.We are in the midst of a global catastrophic situation due to coronavirus outbreak where every day the global death toll is biting the past count. While history has witnessed past pandemics (1-3), 2019 Novel Coronavirus (2019-nCoV) trends to outcompete them all by its rapid transmission in a short period to win the crown. As the name 'corona' (in Latin, it means crown), the accused of the outbreak makes use of a 'crown-shaped' molecular machine, the trimeric spike-protein to drive the virus entry into the host cells. 2019-nCoV is the newest addition of betacoronavirus genus (4). While the sequence and structural similarity to the severe acute respiratory syndrome coronavirus spike (SARS-CoV S) repute the identity of 2019-nCoV spike as SARS-CoV-2 S (5, 6), a recent study reported that the SARS-CoV-2 S has 10-20 fold higher affinity to human angiotensin-converting enzyme 2 (ACE2) receptor than that of SARS-CoV S (7).The large ectodomain of the S glycoprotein of the coronavirus uses the S1 subunit for receptor binding and the trimeric S2 stalk for host-cell membrane fusion (Fig. 1A) (8, 9). In SAR-CoV-2 S glycoprotein, the β-sheet-rich S1 subunit comprises an N terminal domain (NTD) and a receptor-binding domain (RBD) towards its C-terminus (CTD) (Fig. 1B). So far, static structural characterization reported that the RBD of S1 has an intrinsic hinge-like conformational was not certified by peer review)

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“…The rotational alignment of the virus particle studied herein is prefusion and not to be confused with the postfusion diffusive rotational search of the spike-protein unfolding that accompanies binding. 47 …”

Section: Introductionmentioning

confidence: 99%

Coronavirus rotational diffusivity

et al. 2020

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Just 11 weeks after the confirmation of first infection, one team had already discovered and published [D. Wrapp et al. , “Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation,” Science 367 (6483), 1260–1263 (2020)] in exquisite detail about the new coronavirus, along with how it differs from previous viruses. We call the virus particle causing the COVID-19 disease SARS-CoV-2 , a spherical capsid covered with spikes termed peplomers . Since the virus is not motile, it relies on its own random thermal motion, specifically the rotational component of this thermal motion, to align its peplomers with targets. The governing transport property for the virus to attack successfully is thus the rotational diffusivity. Too little rotational diffusivity and too few alignments are produced to properly infect. Too much, and the alignment intervals will be too short to properly infect, and the peplomer is wasted. In this paper, we calculate the rotational diffusivity along with the complex viscosity of four classes of virus particles of ascending geometric complexity: tobacco mosaic, gemini, adeno, and corona. The gemini and adeno viruses share icosahedral bead arrangements, and for the corona virus, we use polyhedral solutions to the Thomson problem to arrange its peplomers. We employ general rigid bead–rod theory to calculate complex viscosities and rotational diffusivities, from first principles, of the virus suspensions. We find that our ab initio calculations agree with the observed complex viscosity of the tobacco mosaic virus suspension. From our analysis of the gemini virus suspension, we learn that the fine detail of the virus structure governs its rotational diffusivity. We find the characteristic time for the adenovirus from general rigid bead–rod theory. Finally, from our analysis of the coronavirus suspension, we learn that its rotational diffusivity descends monotonically with its number of peplomers.

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Rotation-Activated and Cooperative Zipping Characterize Class I Viral Fusion Protein Dynamics

Cited by 5 publications

References 57 publications

Elongation factor-Tu can repetitively engage aminoacyl-tRNA within the ribosome during the proofreading stage of tRNA selection

Elongation factor-Tu can repetitively engage aminoacyl-tRNA within the ribosome during the proofreading stage of tRNA selection

Dynamical asymmetry exposes 2019-nCoV prefusion spike

Coronavirus rotational diffusivity

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