Dynamic Profiling of Binding and Allosteric Propensities of the SARS-CoV-2 Spike Protein with Different Classes of Antibodies: Mutational and Perturbation-Based Scanning Reveals the Allosteric Duality of Functionally Adaptable Hotspots

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

doi:10.1021/acs.jctc.1c00372

Cited by 46 publications

(61 citation statements)

References 113 publications

(228 reference statements)

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“…The latest extensive molecular dynamics (MD) simulations and free-energy landscape mapping studies of the SARS-CoV-2 S proteins and mutants detailed conformational changes and diversity of ensembles, further supporting the notion of enhanced functional and structural plasticity of S proteins [57][58][59][60][61][62][63]. Our recent studies offered evidence that the SARS-CoV-2 spike protein can function as an allosterically regulated machine that exploits plasticity of allosteric hotspots to fine-tune response to antibody binding [64][65][66][67][68][69]. 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.…”

Section: Introductionmentioning

confidence: 66%

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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Section: Introductionmentioning

confidence: 66%

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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“…In a recent study of dynamic profiling of binding and allosteric propensities of the SARS-CoV-2 spike protein with different classes of antibodies, it was seen that RBD mutation sites K417, E484, and N501 correspond to a group of versatile allosteric centers in which small perturbations can modulate collective motions, alter the global allosteric response, and elicit binding resistance. 49 …”

Section: Results and Discussionmentioning

confidence: 99%

Mutation-Induced Long-Range Allosteric Interactions in the Spike Protein Determine the Infectivity of SARS-CoV-2 Emerging Variants

et al. 2021

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The emergence of a variety of highly transmissible SARS-CoV-2 variants, the causative agent of COVID-19, with multiple spike mutations poses serious challenges in overcoming the ongoing deadly pandemic. It is, therefore, essential to understand how these variants gain enhanced ability to evade immune responses with a higher rate of spreading infection. To address this question, here we have individually assessed the effects of SARS-CoV-2 variant-specific spike (S) protein receptor-binding domain (RBD) mutations E484K, K417N, L452Q, L452R, N501Y, and T478K that characterize and differentiate several emerging variants. Despite the hundreds of apparently neutral mutations observed in the domains other than the RBD, we have shown that each RBD mutation site is differentially engaged in an interdomain allosteric network involving mutation sites from a distant domain, affecting interactions with the human receptor angiotensin-converting enzyme-2 (ACE2). This allosteric network couples the residues of the N-terminal domain (NTD) and the RBD, which are modulated by the RBD-specific mutations and are capable of propagating mutation-induced perturbations between these domains through a combination of structural changes and effector-dependent modulations of dynamics. One key feature of this network is the inclusion of compensatory mutations segregated into three characteristically different clusters, where each cluster residue site is allosterically coupled with specific RBD mutation sites. Notably, each RBD mutation acted like a positive allosteric modulator; nevertheless, K417N was shown to have the largest effects among all of the mutations on the allostery and thereby holds the highest binding affinity with ACE2. This result will be useful for designing the targeted control measure and therapeutic efforts aiming at allosteric modulators.

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“…The copyright holder for this preprint (which this version posted July 8, 2021. ; https://doi.org/10.1101/2021.07.07.451538 doi: bioRxiv preprint 8 MD simulations with coevolutionary analysis and network modeling to present evidence that the SARS-CoV-2 spike protein function as allosterically regulated machine that exploits plasticity of allosteric hotspots to fine-tune response to antibody binding. [77][78][79][80][81][82] These studies showed that examining allosteric behavior of the SARS-CoV-2 pike proteins may be useful to uncover functional mechanisms and rationalize the growing body of diverse experimental data.…”

Section: Computer Simulations and Protein Modelingmentioning

confidence: 99%

“…71 Our recent studies combined coarse-grained and atomistic MD simulations with coevolutionary analysis and network modeling to present evidence that the SARS-CoV-2 spike protein function as allosterically regulated machine that exploits plasticity of allosteric hotspots to fine-tune response to antibody binding. 77–82 These studies showed that examining allosteric behavior of the SARS-CoV-2 pike proteins may be useful to uncover functional mechanisms and rationalize the growing body of diverse experimental data. A critical review of computational simulation studies of the SARS-CoV-2 S proteins highlighted the synergies between experiments and simulations, outlining directions for computational biology research in understanding mechanisms of COVID-19 protein targets.…”

Section: Introductionmentioning

confidence: 99%

Atomistic Simulations and Deep Mutational Scanning of Protein Stability and Binding Interactions in the SARS-CoV-2 Spike Protein Complexes with Nanobodies: Molecular Determinants of Mutational Escape Mechanisms

Verkhivker

Agajanian

et al. 2021

Preprint

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Structural and biochemical studies have recently revealed a range of rationally engineered nanobodies with efficient neutralizing capacity against SARS-CoV-2 virus and resilience against mutational escape. In this work, we combined atomistic simulations and conformational dynamics analysis with the ensemble-based mutational profiling of binding interactions for a diverse panel of SARS-CoV-2 spike complexes with nanobodies. Using this computational toolkit we identified dynamic signatures and binding affinity fingerprints for the SARS-CoV-2 spike protein complexes with nanobodies Nb6 and Nb20, VHH E, a pair combination VHH E+U, a biparatopic nanobody VHH VE, and a combination of CC12.3 antibody and VHH V/W nanobodies. Through ensemble-based deep mutational profiling of stability and binding affinities, we identify critical hotspots and characterize molecular mechanisms of SARS-CoV-2 spike protein binding with single ultra-potent nanobodies, nanobody cocktails and biparatopic nanobodies. By quantifying dynamic and energetic determinants of the SARS-CoV-2 S binding with nanobodies, we also examine the effects of circulating variants and escaping mutations. We found that mutational escape mechanisms may be controlled through structurally and energetically adaptable binding hotspots located in the host receptor-accessible binding epitope that are dynamically coupled to the stability centers in the distant epitope targeted by VHH U/V/W nanobodies. The results of this study suggested a mechanism in which through cooperative dynamic changes, nanobody combinations and biparatopic nanobody can modulate the global protein response and induce the increased resilience to common escape mutants.

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Dynamic Profiling of Binding and Allosteric Propensities of the SARS-CoV-2 Spike Protein with Different Classes of Antibodies: Mutational and Perturbation-Based Scanning Reveals the Allosteric Duality of Functionally Adaptable Hotspots

Cited by 46 publications

References 113 publications

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

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

Mutation-Induced Long-Range Allosteric Interactions in the Spike Protein Determine the Infectivity of SARS-CoV-2 Emerging Variants

Atomistic Simulations and Deep Mutational Scanning of Protein Stability and Binding Interactions in the SARS-CoV-2 Spike Protein Complexes with Nanobodies: Molecular Determinants of Mutational Escape Mechanisms

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