Structure-activity relationships of B.1.617 and other SARS-CoV-2 spike variants

Yang, Tzu-Jing; Yu, Pei-Yu; Chang, Yuan-Chih; Chang, Ning-En; Tsai, Yu-Xi; Liang, Kang-Hao; Drączkowski, Piotr; Lin, Bertina; Wang, Yongsheng; Chien, Yu-Chun; Khoo, Kay‐Hooi; Wu, Han‐Chung; Hsu, Shang‐Te Danny

doi:10.1101/2021.09.12.459978

Cited by 26 publications

(48 citation statements)

References 48 publications

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“…For example, Cai et al have reported that the affinity of the Beta S to monomeric ACE2 (K D = 71.4 nM) increased as compared to that of the G614 S (K D = 124.0 nM) 30 . It should be mentioned that, for a given variant S protein, its absolute K D values generated from different studies 29,30,[42][43][44][45][46] , including two studies recently reported on BioRxiv 57,58 , may vary significantly, likely due to multiple factors such as the method used (BLI or SPR), S protein construct (full-length S or prefusion-stabilized S ectodomain), ACE2 form (monomeric or dimeric), the protein used to load the sensors (ACE2 or S), and even binding temperature. For example, it has been reported that the full-length G614 S had a K D value of 12.8 nM to dimeric ACE2 but its K D value to monomeric ACE2 was 124 nM 30 .…”

Section: Resultsmentioning

confidence: 99%

Conformational dynamics of the Beta and Kappa SARS-CoV-2 spike proteins and their complexes with ACE2 receptor revealed by cryo-EM

Wang

Qin

et al. 2021

Nat Commun

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The emergence of SARS-CoV-2 Kappa and Beta variants with enhanced transmissibility and resistance to neutralizing antibodies has created new challenges for the control of the ongoing COVID-19 pandemic. Understanding the structural nature of Kappa and Beta spike (S) proteins and their association with ACE2 is of significant importance. Here we present two cryo-EM structures for each of the Kappa and Beta spikes in the open and open-prone transition states. Compared with wild-type (WT) or G614 spikes, the two variant spikes appear more untwisted/open especially for Beta, and display a considerable population shift towards the open state as well as more pronounced conformational dynamics. Moreover, we capture four conformational states of the S-trimer/ACE2 complex for each of the two variants, revealing an enlarged conformational landscape for the Kappa and Beta S-ACE2 complexes and pronounced population shift towards the three RBDs up conformation. These results implicate that the mutations in Kappa and Beta may modify the kinetics of receptor binding and viral fusion to improve virus fitness. Combined with biochemical analysis, our structural study shows that the two variants are enabled to efficiently interact with ACE2 receptor despite their sensitive ACE2 binding surface is modified to escape recognition by some potent neutralizing MAbs. Our findings shed new light on the pathogenicity and immune evasion mechanism of the Beta and Kappa variants.

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Section: Resultsmentioning

confidence: 99%

Conformational dynamics of the Beta and Kappa SARS-CoV-2 spike proteins and their complexes with ACE2 receptor revealed by cryo-EM

Wang

Qin

et al. 2021

Nat Commun

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“…The enhanced mobility of this functional RBD region is important to enable spontaneous transitions between the closed and open forms required for engagement with the ACE2 receptor. It is worth noting that the conformational dynamics profiles also revealed the increased thermal "breezing" that is spread across both S1 and S2 subunits in the S-B.1.1.7 and S-B.1.351 closed states (Figure 2A), providing support for the notion that these mutational variants may perturb and destabilize the closed form, thereby shifting the equilibrium to a more dynamic open form [34][35][36]. The root mean square fluctuation (RMSF) profiles for the 1 RBD-up open states were similar for S-G614 and S-B.1.1.7 conformations, while larger fluctuations were observed in the S-B.1.351 structure (Figure 2B).…”

Section: Atomistic Modeling and Simulations Reveal Distinct Conformational Flexibility Patterns Of The Sars-cov-2 S Mutant Variantsmentioning

confidence: 69%

“…A significant heterogeneity and plasticity of the conformational landscapes for the SARS-CoV-2 S proteins was recently unveiled in the large-scale structural investigation that reported 38 cryo-EM structures of the B.1.351, B.1.1.28/P.1, B.1.617.2 (Delta), and B.1.617.1 (Kappa) variants, featuring a broad spectrum of the RBD-up conformations intrinsically present in the apo form [36]. In particular, S-B.1.351 variant displayed a highly populated fully open state with all three RBDs in the up conformation in addition to significant fractions of the partially open states (1 RBD-up or 2 RBD-up) [36]. Importantly, among all the examined variants only S-B.1.351 exhibited a fully open 3 RBD-up conformation that resembles the structure of the fully open S-G614 variant.…”

Section: Introductionmentioning

confidence: 99%

Conformational Flexibility and Local Frustration in the Functional States of the SARS-CoV-2 Spike B.1.1.7 and B.1.351 Variants: Mutation-Induced Allosteric Modulation Mechanism of Functional Dynamics and Protein Stability

Verkhivker

2022

IJMS

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Structural and functional studies of the SARS-CoV-2 spike proteins have recently determined distinct functional states of the B.1.1.7 and B.1.351 spike variants, providing a molecular framework for understanding the mechanisms that link the effect of mutations with the enhanced virus infectivity and transmissibility. A detailed dynamic and energetic analysis of these variants was undertaken in the present work to quantify the effects of different mutations on functional conformational changes and stability of the SARS-CoV-2 spike protein. We employed the efficient and accurate coarse-grained (CG) simulations of multiple functional states of the D614G mutant, B.1.1.7 and B.1.351 spike variants to characterize conformational dynamics of the SARS-CoV-2 spike proteins and identify dynamic signatures of the functional regions that regulate transitions between the closed and open forms. By combining molecular simulations with full atomistic reconstruction of the trajectories and the ensemble-based mutational frustration analysis, we characterized how the intrinsic flexibility of specific spike regions can control functional conformational changes required for binding with the host-cell receptor. Using the residue-based mutational scanning of protein stability, we determined protein stability hotspots and identified potential energetic drivers favoring the receptor-accessible open spike states for the B.1.1.7 and B.1.351 spike variants. The results suggested that modulation of the energetic frustration at the inter-protomer interfaces can serve as a mechanism for allosteric couplings between mutational sites and the inter-protomer hinges of functional motions. The proposed mechanism of mutation-induced energetic frustration may result in greater adaptability and the emergence of multiple conformational states in the open form. This study suggested that SARS-CoV-2 B.1.1.7 and B.1.351 variants may leverage the intrinsic plasticity of functional regions in the spike protein for mutation-induced modulation of protein dynamics and allosteric regulation to control binding with the host cell receptor.

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“…This limitation is due to the Gaussian representation currently required by the underlying TensorFlow system." implemented on cryoSparc (Punjani et al, 2017), another package as popular as Relion, it has received wide attention in the cryo-EM community to make immediate impact on COVID-19 research (Yang et al, 2021). It is also noted that a PCA approach developed by Stark group with implementation on COW has been available (Haselbach et al, 2017) for facilitating investigation on conformation dynamics (Haselbach et al, 2017) or energy landscape (Haselbach et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Cryo-EM Analyses Permit Visualization of Structural Polymorphism of Biological Macromolecules

et al. 2021

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The functions of biological macromolecules are often associated with conformational malleability of the structures. This phenomenon of chemically identical molecules with different structures is coined structural polymorphism. Conventionally, structural polymorphism is observed directly by structural determination at the density map level from X-ray crystal diffraction. Although crystallography approach can report the conformation of a macromolecule with the position of each atom accurately defined in it, the exploration of structural polymorphism and interpreting biological function in terms of crystal structures is largely constrained by the crystal packing. An alternative approach to studying the macromolecule of interest in solution is thus desirable. With the advancement of instrumentation and computational methods for image analysis and reconstruction, cryo-electron microscope (cryo-EM) has been transformed to be able to produce “in solution” structures of macromolecules routinely with resolutions comparable to crystallography but without the need of crystals. Since the sample preparation of single-particle cryo-EM allows for all forms co-existing in solution to be simultaneously frozen, the image data contain rich information as to structural polymorphism. The ensemble of structure information can be subsequently disentangled through three-dimensional (3D) classification analyses. In this review, we highlight important examples of protein structural polymorphism in relation to allostery, subunit cooperativity and function plasticity recently revealed by cryo-EM analyses, and review recent developments in 3D classification algorithms including neural network/deep learning approaches that would enable cryo-EM analyese in this regard. Finally, we brief the frontier of cryo-EM structure determination of RNA molecules where resolving the structural polymorphism is at dawn.

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Structure-activity relationships of B.1.617 and other SARS-CoV-2 spike variants

Cited by 26 publications

References 48 publications

Conformational dynamics of the Beta and Kappa SARS-CoV-2 spike proteins and their complexes with ACE2 receptor revealed by cryo-EM

Conformational dynamics of the Beta and Kappa SARS-CoV-2 spike proteins and their complexes with ACE2 receptor revealed by cryo-EM

Conformational Flexibility and Local Frustration in the Functional States of the SARS-CoV-2 Spike B.1.1.7 and B.1.351 Variants: Mutation-Induced Allosteric Modulation Mechanism of Functional Dynamics and Protein Stability

Cryo-EM Analyses Permit Visualization of Structural Polymorphism of Biological Macromolecules

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