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, Gennady M.; Agajanian, Steve; Öztaş, Deniz Yaşar; Gupta, Grace

doi:10.1080/07391102.2021.1933594

Cited by 12 publications

(13 citation statements)

References 114 publications

(150 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We also point out that our simulation of the WT spike can, by fiat, only identify the residue to be mutated, but not the amino acid to which the residue will be mutated. However, both experimental and computer simulation studies have already established that D614G, A570D, and a few other mutations transform the dynamics of the RBD and favor an "up" state (54,55,59,61,72). In the current work, we highlighted a set of residues which show high correlation with RBD opening motion.…”

Section: Concluding Discussionmentioning

confidence: 71%

“…The D614G mutant prefers the one RBD "up" state ∼7 times more than the "three-down" configuration, while they are equally likely in the WT strain (54). The specific role of the D614G mutation was recently also established by coarse-grained MD study (72). Our model predicted the D614 residue as a key player in RBD dynamics from physicsbased atomistic simulations without any prior knowledge of the mutation profile of the spike.…”

Section: Concluding Discussionmentioning

confidence: 77%

“…This indicates that the down-to-up conformational change is indeed necessary for binding to ACE2. While we did not thoroughly study the dynamics of actual mutant spike proteins, the role of specific point mutations in the dynamics of RBD of the spike protein has been explored using MD simulation in the literature (60,72).…”

Section: Concluding Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Distant residues modulate conformational opening in SARS-CoV-2 spike protein

Ray

Andricioaei

2021

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

View full text Add to dashboard Cite

Infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) involves the attachment of the receptor-binding domain (RBD) of its spike proteins to the ACE2 receptors on the peripheral membrane of host cells. Binding is initiated by a down-to-up conformational change in the spike protein, the change that presents the RBD to the receptor. To date, computational and experimental studies that search for therapeutics have concentrated, for good reason, on the RBD. However, the RBD region is highly prone to mutations, and is therefore a hotspot for drug resistance. In contrast, we here focus on the correlations between the RBD and residues distant to it in the spike protein. This allows for a deeper understanding of the underlying molecular recognition events and prediction of the highest-effect key mutations in distant, allosteric sites, with implications for therapeutics. Also, these sites can appear in emerging mutants with possibly higher transmissibility and virulence, and preidentifying them can give clues for designing pan-coronavirus vaccines against future outbreaks. Our model, based on time-lagged independent component analysis (tICA) and protein graph connectivity network, is able to identify multiple residues that exhibit long-distance coupling with the RBD opening. Residues involved in the most ubiquitous D614G mutation and the A570D mutation of the highly contagious UK SARS-CoV-2 variant are predicted ab initio from our model. Conversely, broad-spectrum therapeutics like drugs and monoclonal antibodies can target these key distant-but-conserved regions of the spike protein.

show abstract

Section: Concluding Discussionmentioning

confidence: 71%

Section: Concluding Discussionmentioning

confidence: 77%

See 1 more Smart Citation

Distant residues modulate conformational opening in SARS-CoV-2 spike protein

Ray

Andricioaei

2021

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

View full text Add to dashboard Cite

show abstract

“…Lineage B.1.351 4 was first identified in November 2020 in South Africa and is characterized by two additional substitutions of likely significance in RBD, namely, K417N and E484K. The former is predicted to disrupt a salt bridge with D30 of ACE2, a characteristic of SARS-CoV-2 in distinction to severe acute respiratory syndrome coronavirus (SARS-CoV-1), but may not impact on binding, whereas the latter, which might disrupt the interaction of RBD with K31 of human ACE2, may enhance ACE2 binding 2,5 . On 1 March 2021, this lineage accounted for 5% of all current sequences globally, and 100% of those identified in South Africa.…”

mentioning

confidence: 99%

Two doses of SARS-CoV-2 vaccination induce robust immune responses to emerging SARS-CoV-2 variants of concern

et al. 2021

View full text Add to dashboard Cite

The extent to which immune responses to natural infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and immunization with vaccines protect against variants of concern (VOC) is of increasing importance. Accordingly, here we analyse antibodies and T cells of a recently vaccinated, UK cohort, alongside those recovering from natural infection in early 2020. We show that neutralization of the VOC compared to a reference isolate of the original circulating lineage, B, is reduced: more profoundly against B.1.351 than for B.1.1.7, and in responses to infection or a single dose of vaccine than to a second dose of vaccine. Importantly, high magnitude T cell responses are generated after two vaccine doses, with the majority of the T cell response directed against epitopes that are conserved between the prototype isolate B and the VOC. Vaccination is required to generate high potency immune responses to protect against these and other emergent variants.

show abstract

“…These studies showed that examining allosteric behavior of the SARS-CoV-2 S proteins may be useful to uncover functional mechanisms and rationalize the growing body of diverse experimental data. In particular, using an atomistic-based model of signal transmission in the SARS-CoV-2 S proteins, we determined that the D614G mutation can exert its effect through allosterically induced changes on stability and communications in the residue interaction networks [70,71]. Previous computational studies also identified residues that exhibit long-distance couplings with the RBD opening that included sites harboring functional mutations D614G and A570D shared across SARS-CoV-2 S protein variants [59].…”

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

View full text Add to dashboard Cite

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.

show abstract

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

Cited by 12 publications

References 114 publications

Distant residues modulate conformational opening in SARS-CoV-2 spike protein

Distant residues modulate conformational opening in SARS-CoV-2 spike protein

Two doses of SARS-CoV-2 vaccination induce robust immune responses to emerging SARS-CoV-2 variants of concern

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

Contact Info

Product

Resources

About