Functional importance of the D614G mutation in the SARS-CoV-2 spike protein

Jackson, Cody B.; Zhang, Lizhou; Farzan, Michael; Choe, Hyeryun

doi:10.1016/j.bbrc.2020.11.026

Cited by 88 publications

(107 citation statements)

References 106 publications

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“… 133 It is worth noting that molecular mechanisms underlying the D614G effect are not well understood. 134 Several studies suggested that D614G may affect the intraprotomer energetics and favor a “one-up” open conformation by eliciting contract changes in the CTD1 and FP regions. 135 , 136 In support of our results, recent cryo-EM structures of SARS-CoV-2 S mutants revealed an allosteric effect that seemingly small D614G changes in the SD2 domain have on RBD dynamics, suggesting that SD2 regions may be involved in modulating RBD transitions between up and down conformations.…”

Section: Resultsmentioning

confidence: 99%

Dynamic Network Modeling of Allosteric Interactions and Communication Pathways in the SARS-CoV-2 Spike Trimer Mutants: Differential Modulation of Conformational Landscapes and Signal Transmission via Cascades of Regulatory Switches

2021

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The rapidly growing body of structural and biochemical studies of the SARS-CoV-2 spike glycoprotein has revealed a variety of distinct functional states with radically different arrangements of the receptor-binding domain, highlighting a remarkable function-driven conformational plasticity and adaptability of the spike proteins. In this study, we examined molecular mechanisms underlying conformational and dynamic changes in the SARS-CoV-2 spike mutant trimers through the lens of dynamic analysis of allosteric interaction networks and atomistic modeling of signal transmission. Using an integrated approach that combined coarsegrained molecular simulations, protein stability analysis, and perturbation-based modeling of residue interaction networks, we examined how mutations in the regulatory regions of the SARS-CoV-2 spike protein can differentially affect dynamics and allosteric signaling in distinct functional states. The results of this study revealed key functional regions and regulatory centers that govern collective dynamics, allosteric interactions, and control signal transmission in the SARS-CoV-2 spike proteins. We found that the experimentally confirmed regulatory hotspots that dictate dynamic switching between conformational states of the SARS-CoV-2 spike protein correspond to the key hinge sites and global mediating centers of the allosteric interaction networks. The results of this study provide a novel insight into allosteric regulatory mechanisms of SARS-CoV-2 spike proteins showing that mutations at the key regulatory positions can differentially modulate distribution of states and determine topography of signal communication pathways operating through state-specific cascades of control switch points. This analysis provides a plausible strategy for allosteric probing of the conformational equilibrium and therapeutic intervention by targeting specific hotspots of allosteric interactions and communications in the SARS-CoV-2 spike proteins.

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Section: Resultsmentioning

confidence: 99%

Dynamic Network Modeling of Allosteric Interactions and Communication Pathways in the SARS-CoV-2 Spike Trimer Mutants: Differential Modulation of Conformational Landscapes and Signal Transmission via Cascades of Regulatory Switches

2021

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“…[39][40][41] The latest biochemical studies provided a compelling evidence of a phenotypic advantage and the enhanced infectivity conferred by the D614G mutation. 42 The recent structural and biochemical studies suggested that the This study also demonstrated that the S-D614G mutant could modulate conformational population of the S protein and result in the increased furin cleavage efficiency of the S ectodomain. In addition, these experiments suggested that the D614G mutation in the SD2 domain can induce allosteric effect leading to coordinated movements and structural shifts between the up and down RBD conformations.…”

Section: Sars-cov-2 S Protein Between a Spectrum Of Closed And Receptmentioning

confidence: 73%

Computational Analysis of Protein Stability and Allosteric Interaction Networks in Distinct Conformational Forms of the SARS-CoV-2 Spike D614G Mutant: Reconciling Functional Mechanisms through Allosteric Model of Spike Regulation

Verkhivker

Agajanian

Oztas

et al. 2021

Preprint

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Structural and biochemical studies SARS-CoV-2 spike mutants with the enhanced infectivity have attracted significant attention and offered several mechanisms to explain the experimental data. The development of a unified view and a working model which is consistent with the diverse experimental data is an important focal point of the current work. In this study, we used an integrative computational approach to examine molecular mechanisms underlying functional effects of the D614G mutation by exploring atomistic modeling of the SARS-CoV-2 spike proteins as allosteric regulatory machines. We combined coarse-grained simulations, protein stability and dynamic fluctuation communication analysis along with network-based community analysis to simulate structures of the native and mutant SARS-CoV-2 spike proteins in different functional states. The results demonstrated that the D614 position anchors a key regulatory cluster that dictates functional transitions between open and closed states. Using molecular simulations and mutational sensitivity analysis of the SARS-CoV-2 spike proteins we showed that the D614G mutation can improve stability of the spike protein in both closed and open forms, but shifting thermodynamic preferences towards the open mutant form. The results offer support to the reduced shedding mechanism of S1 domain as a driver of the increased infectivity triggered by the D614G mutation. Through distance fluctuations communication analysis, we probed stability and allosteric communication propensities of protein residues in the native and mutant SARS-CoV-2 spike proteins, providing evidence that the D614G mutation can enhance long-range signaling of the allosteric spike engine. By employing network community analysis of the SARS-CoV-2 spike proteins, our results revealed that the D614G mutation can promote the increased number of stable communities and allosteric hub centers in the open form by reorganizing and enhancing the stability of the S1-S2 inter-domain interactions and restricting mobility of the S1 regions. This study provides atomistic-based view of the allosteric interactions and communications in the SARS-CoV-2 spike proteins, suggesting that the D614G mutation can exert its primary effect through allosterically induced changes on stability and communications in the residue interaction networks.

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“…Despite this uniquely high fidelity of replication, a number of mutations to the SARS-CoV-2 genome have been observed throughout the present course of the COVID-19 pandemic. Among SARS-related coronaviruses (Sarbecoviruses), only SARS-CoV-2 possesses a polybasic furin cleavage site at the S1-S2 junction in the Spike (S) protein, which is critical to human infection and transmission [ 6 , 7 ]. However, the furin cleavage site may have rendered the S protein less stable and therefore the virus may need mutation(s) to compensate for this instability.…”

mentioning

confidence: 99%

“…However, the furin cleavage site may have rendered the S protein less stable and therefore the virus may need mutation(s) to compensate for this instability. The acute selective pressure of S protein instability, which has been an Achilles’ heel of the SARS-CoV-2, most probably was resolved by the highly emphasized D614 G mutation [ 7 ].…”

mentioning

confidence: 99%