Significance of the RBD mutations in the SARS-CoV-2 omicron: from spike opening to antibody escape and cell attachment

Hossen, Md Lokman; Baral, Prabin; Sharma, Tej; Gerstman, Bernard S.; Chapagain, Prem P.

doi:10.1039/d2cp00169a

Cited by 25 publications

(35 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Using the replica-exchange MD simulations with solute tempering of selected surface charged residues, the conformational landscapes of the full-length S protein trimers were investigated, unveiling previously unknown cryptic pockets and the meta-stable intermediate states [57]. A number of computational studies employed atomistic simulations and binding energy analysis to examine the interactions between the S-RBD Omicron and the ACE2 receptor [58-62]. All-atom MD simulations of the S Omicron trimer and the Omicron RBD–ACE2 complexes suggested that the Omicron mutations may have evolved to inflict a greater infectivity using a combination of more efficient RBD opening, the increased binding affinity with ACE2, and optimized capacity for antibody escape [58].…”

Section: Introductionmentioning

confidence: 99%

Atomistic Simulations and Network-Based Energetic Profiling of Binding and Allostery in the SARS-CoV-2 Spike Omicron BA.1, BA.1.1, BA.2 and BA.3 Subvariant Complexes with the Host Receptor: Revealing Hidden Functional Roles of the Binding Hotspots in Mediating Epistatic Effects and Long-Range Communication with Allosteric Pockets

Verkhivker

Agajanian

Krishnan

et al. 2022

Preprint

View full text Add to dashboard Cite

In this study, we performed all-atom MD simulations of the RBD-ACE2 complexes for BA.1, BA.1.1, BA.2, an BA.3 Omicron subvariants, conducted a systematic mutational scanning of the RBD-ACE2 binding interfaces and analysis of electrostatic effects. The binding free energy computations of the Omicron RBD-ACE2 complexes and comprehensive examination of the electrostatic interactions quantify the driving forces of binding and provide new insights into energetic mechanisms underlying evolutionary differences between Omicron variants. A systematic mutational scanning of the RBD residues determines the protein stability centers and binding energy hotpots in the Omicron RBD-ACE2 complexes. By employing the ensemble-based global network analysis, we proposed a community-based topological model of the Omicron RBD interactions that characterized functional roles of the Omicron mutational sites in mediating non-additive epistatic effects of mutations. Our findings suggested that non-additive contributions to the binding affinity may be mediated by R493, Y498, and Y501 sites and are greater for the Omicron BA.1.1 and BA.2 complexes that display the strongest ACE2 binding affinity among the Omicron subvariants. A network-centric adaptation model of the reversed allosteric communication is unveiled in this study that established a robust connection between allosteric network hotspots and potential allosteric binding pockets. Using this approach, we demonstrated that mediating centers of long-range interactions could anchor the experimentally validated allosteric binding pockets. Through an array of complementary approaches and proposed models, this comprehensive and multi-faceted computational study revealed and quantified multiple functional roles of the key Omicron mutational site R493, R498 and Y501 acting as binding energy hotspots, drivers of electrostatic interactions as well as mediators of epistatic effects and long-range communications with the allosteric pockets.

show abstract

Section: Introductionmentioning

confidence: 99%

Atomistic Simulations and Network-Based Energetic Profiling of Binding and Allostery in the SARS-CoV-2 Spike Omicron BA.1, BA.1.1, BA.2 and BA.3 Subvariant Complexes with the Host Receptor: Revealing Hidden Functional Roles of the Binding Hotspots in Mediating Epistatic Effects and Long-Range Communication with Allosteric Pockets

Verkhivker

Agajanian

Krishnan

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…In silico modelling of the spike protein RGD site (403–405) located with the receptor-binding domain (RBD) has predicted numerous points of contact with its putative integrin receptor, αVβ3 [ 1 ]. It has been proposed that select mutations within SARS-CoV-2 variants of concern enable a more wide-open RBD, thereby increasing the likelihood of host–virus recognition [ 11 ]. We performed ELISA-based assays to confirm the direct binding between integrin αVβ3 and spike protein of wild-type, Delta (B.1.617.2), and Omicron (B.1.1.529) in the presence or absence of the cyclic RGD peptide compound Cilengitide and neutralizing monoclonal antibodies which target the active site of the αVβ3 integrin or the β3 subunit.…”

Section: Resultsmentioning

confidence: 99%

Molecular Cross-Talk between Integrins and Cadherins Leads to a Loss of Vascular Barrier Integrity during SARS-CoV-2 Infection

Nader

Kerrigan

2022

Viruses

View full text Add to dashboard Cite

The vascular barrier is heavily injured following SARS-CoV-2 infection and contributes enormously to life-threatening complications in COVID-19. This endothelial dysfunction is associated with the phlogistic phenomenon of cytokine storms, thrombotic complications, abnormal coagulation, hypoxemia, and multiple organ failure. The mechanisms surrounding COVID-19 associated endotheliitis have been widely attributed to ACE2-mediated pathways. However, integrins are emerging as possible receptor candidates for SARS-CoV-2, and their complex intracellular signaling events are essential for maintaining endothelial homeostasis. Here, we showed that the spike protein of SARS-CoV-2 depends on its RGD motif to drive barrier dysregulation by hijacking integrin αVβ3, expressed on human endothelial cells. This triggers the redistribution and internalization of major junction protein VE-Cadherin which leads to the barrier disruption phenotype. Both extracellular and intracellular inhibitors of integrin αVβ3 prevented these effects, similarly to the RGD-cyclic peptide compound Cilengitide, which suggests that the spike protein—through its RGD motif—binds to αVβ3 and elicits vascular leakage events. These findings support integrins as an additional receptor for SARS-CoV-2, particularly as integrin engagement can elucidate many of the adverse endothelial dysfunction events that stem from COVID-19.

show abstract

Section: Introductionmentioning

confidence: 99%

“…81 Computer simulations of the S Omicron RBD structures and complexes with ACE2 detailed the molecular determinants of the enhanced interfacial interactions mediated by the Omicron mutational sites. 82,83 Recent insightful evolutionary analysis 84 suggested that the mechanisms underlying emergence of the Omicron variant involves multiple fitness trade-offs including balancing between immune escape [85][86][87] and binding affinity for ACE2 proteins 33,55,56 and between the requirements to switch to the RBD-up configuration for ACE2 recognition and the increased stabilization of the closed form that prevents binding of neutralizing antibodies. Despite of the rapidly growing body of computational studies of the S Omicron proteins the specific regulatory roles of individual Omicron mutations remain unclear, and the potential mechanism underlying a cooperative cross-talk between mutational sites has not been examined at the atomistic level.…”

Section: Introductionmentioning

confidence: 99%

Hierarchical Computational Modeling and Dynamic Network Analysis of Allosteric Regulation in the SARS-CoV-2 Spike Omicron Trimer Structures: Omicron Mutations Cooperate to Allosterically Control Balance of Protein Stability and Conformational Adaptability

Verkhivker

Agajanian

Kassab

et al. 2022

Preprint

View full text Add to dashboard Cite

Structural and computational studies of the Omicron spike protein in various functional states and complexes provided important insights into molecular mechanisms underlying binding, high transmissibility, and escaping immune defense. However, the regulatory roles and functional coordination of the Omicron mutations are poorly understood and often ignored in the proposed mechanisms. In this work, we explored the hypothesis that the SARS-CoV-2 spike protein can function as a robust allosterically regulated machinery in which Omicron mutational sites are dynamically coupled and form a central engine of the allosteric network that regulates the balance between conformational plasticity, protein stability, and functional adaptability. In this study, we employed coarse-grained dynamics simulations of multiple full-length SARS-CoV-2 spike Omicron trimers structures in the closed and open states with the local energetic frustration analysis and collective dynamics mapping to understand the determinants and key hotspots driving the balance of protein stability and conformational adaptability. We have found that the Omicron mutational sites at the inter-protomer regions form regulatory clusters that control functional transitions between the closed and open states. Through perturbation-based modeling of allosteric interaction networks and diffusion analysis of communications in the closed and open spike states, we quantify the allosterically regulated activation mechanism and uncover specific regulatory roles of the Omicron mutations. The network modeling demonstrated that Omicron mutations form the inter-protomer electrostatic bridges that connect local stable communities and function as allosteric switches of signal transmission. The results of this study are consistent with the experiments, revealing distinct and yet complementary role of the Omicron mutational sites as a network of hotspots that enable allosteric modulation of structural stability and conformational changes which are central for spike activation and virus transmissibility.

show abstract

Significance of the RBD mutations in the SARS-CoV-2 omicron: from spike opening to antibody escape and cell attachment

Abstract: We computationally investigated the role of the Omicron RBD mutations on its structure and interactions with surrounding domains in the spike trimer as well as with ACE2. Our results suggest...

Cited by 25 publications

References 58 publications

Molecular Cross-Talk between Integrins and Cadherins Leads to a Loss of Vascular Barrier Integrity during SARS-CoV-2 Infection

Hierarchical Computational Modeling and Dynamic Network Analysis of Allosteric Regulation in the SARS-CoV-2 Spike Omicron Trimer Structures: Omicron Mutations Cooperate to Allosterically Control Balance of Protein Stability and Conformational Adaptability

Contact Info

Product

Resources

About