Frustration-driven allosteric regulation and signal transmission in the SARS-CoV-2 spike omicron trimer structures: a crosstalk of the omicron mutation sites allosterically regulates tradeoffs of protein stability and conformational adaptability

Verkhivker, Gennady M.; Agajanian, Steve; Kassab, Ryan; Krishnan, Keerthi

doi:10.1039/d2cp01893d

Cited by 11 publications

(17 citation statements)

References 117 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As mutations serve as markers of genetic variations, it is difficult to quantify their stability; however, mutational effects on the proteins’ general stability can be predicted. A recently published article has demonstrated this point, where the S protein mutations within Omicron variant have been found to play roles in allosterically regulating the stability, conformational flexibility and structural adaptability of the protein [28].…”

Section: Resultsmentioning

confidence: 99%

Molecular Investigations of Selected Spike Protein Mutations in SARS-CoV-2: Delta and Omicron Variants and Omicron Subvariants

Roy

2022

Preprint

View full text Add to dashboard Cite

Among the multiple SARS-CoV-2 variants recently reported, the delta variant has generated most perilous and widespread effects. Another variant, omicron, has been identified specifically for its high transmissibility. Omicron contains numerous spike (S) protein mutations and in numbers much larger than those of its predecessor variants. BA.2, a sub variant of omicron, has recently emerged with more spreadable infectivity as compared to the original omicron species. BA.2 also contains several new and additional mutations in its spike protein, and represents the globally most prevalent form of SARS-CoV-2 at the present time.In this report we discuss some essential structural aspects and time-based structure changes of a selected set of spike protein mutations within the delta and omicron variants, including those of omicron BA.2. The expected impact of multiple-point mutations within the spike protein’s receptor-binding domain (RBD) and S1 are also discussed. It is expected that the structural data discussed in this report will be helpful to identify drug targets and to neutralize antibodies for the evolving variants/sub variants of SARS-CoV-2.

show abstract

Section: Resultsmentioning

confidence: 99%

Molecular Investigations of Selected Spike Protein Mutations in SARS-CoV-2: Delta and Omicron Variants and Omicron Subvariants

Roy

2022

Preprint

View full text Add to dashboard Cite

show abstract

“…By examining conformational landscapes and the residue interaction networks in the SARS-CoV-2 Omicron spike protein structures, we have shown that the Omicron mutational sites are dynamically coupled and form a central engine of the allosterically regulated spike machinery that regulates the balance between conformational plasticity, protein stability, and functional adaptability. 141 MD simulations demonstrated an allosteric crosstalk within the RBD in the apo-and the ACE2 receptor-bound states. 142 Allosteric interactions between SARS-CoV-2 spike mutational sites were also confirmed in extensive MD simulations, suggesting that the interplay of spatially proximal local interactions and long-range communications between sites of escape mutations can represent an evolutionary strategy employed by the virus to modulate virulence of emerging SARS-CoV-2 variants.…”

Section: ■ Allosteric Regulation Models and Machine Learning In Struc...mentioning

confidence: 93%

“…These studies provided compelling evidence that the SARS-CoV-2 S protein can function as a functionally adaptable allosterically regulated machine that exploits plasticity of allosteric centers to fine-tune responses to antibody binding, where the experimentally confirmed regulatory hotspots correspond to the global mediating centers of the allosteric interaction networks (Figure ). By examining conformational landscapes and the residue interaction networks in the SARS-CoV-2 Omicron spike protein structures, we have shown that the Omicron mutational sites are dynamically coupled and form a central engine of the allosterically regulated spike machinery that regulates the balance between conformational plasticity, protein stability, and functional adaptability . MD simulations demonstrated an allosteric crosstalk within the RBD in the apo- and the ACE2 receptor-bound states .…”

Section: Allosteric Regulation Models and Machine Learning In Structu...mentioning

confidence: 99%

Exploring and Learning the Universe of Protein Allostery Using Artificial Intelligence Augmented Biophysical and Computational Approaches

Agajanian

Alshahrani

Bai

et al. 2023

J. Chem. Inf. Model.

Self Cite

View full text Add to dashboard Cite

Allosteric mechanisms are commonly employed regulatory tools used by proteins to orchestrate complex biochemical processes and control communications in cells. The quantitative understanding and characterization of allosteric molecular events are among major challenges in modern biology and require integration of innovative computational experimental approaches to obtain atomistic-level knowledge of the allosteric states, interactions, and dynamic conformational landscapes. The growing body of computational and experimental studies empowered by emerging artificial intelligence (AI) technologies has opened up new paradigms for exploring and learning the universe of protein allostery from first principles. In this review we analyze recent developments in high-throughput deep mutational scanning of allosteric protein functions; applications and latest adaptations of Alpha-fold structural prediction methods for studies of protein dynamics and allostery; new frontiers in integrating machine learning and enhanced sampling techniques for characterization of allostery; and recent advances in structural biology approaches for studies of allosteric systems. We also highlight recent computational and experimental studies of the SARS-CoV-2 spike (S) proteins revealing an important and often hidden role of allosteric regulation driving functional conformational changes, binding interactions with the host receptor, and mutational escape mechanisms of S proteins which are critical for viral infection. We conclude with a summary and outlook of future directions suggesting that AI-augmented biophysical and computer simulation approaches are beginning to transform studies of protein allostery toward systematic characterization of allosteric landscapes, hidden allosteric states, and mechanisms which may bring about a new revolution in molecular biology and drug discovery.

show abstract

“…No reuse allowed without permission. conformational landscapes and dynamic interaction networks in the SARS-CoV-2 Omicron structures, we found that Omicron mutational sites can be dynamically coupled through short and long-range interactions forming an adaptive allosteric network that controls balance and tradeoffs between conformational plasticity, protein stability, and functional adaptability [83].…”

Section: Introductionmentioning

confidence: 93%

“…The enhanced MD simulations examined the stability of the S-D 614G variant showing that the mutation orders the 630-loop structure and allosterically alters global interactions between RBDs, forming an asymmetric and mobile down conformation and facilitating transitions toward up conformation [75]. Our previous studies revealed that the SARS-CoV-2 S protein can function as an allosteric regulatory machinery that is controlled by stable allosteric hotspots to modulate specific regulatory and binding functions [76][77][78][79][80][81][82][83]. By examining (which was not certified by peer review) is the author/funder.…”

Section: Introductionmentioning

confidence: 99%

Balancing Functional Tradeoffs between Protein Stability and ACE2 Binding in the SARS-CoV-2 Omicron BA.2, BA.2.75 and XBB Lineages : Dynamics-Based Network Models Reveal Epistatic Effects Modulating Compensatory Dynamic and Energetic Changes

Verkhivker

Alshahrani

Gupta

2023

Preprint

Self Cite

View full text Add to dashboard Cite

The evolutionary and functional studies suggested that the emergence of the Omicron variants can be determined by multiple fitness trade-offs including the immune escape, binding affinity for ACE2, conformational plasticity, protein stability and allosteric modulation. In this study, we systematically characterize conformational dynamics, protein stability and binding affinities of the SARS-CoV-2 Spike Omicron complexes with the host receptor ACE2 for BA.2 , BA.2.75, XBB.1 and XBB.1.5 variants. We combined multiscale molecular simulations and dynamic analysis of allosteric interactions together with the ensemble-based mutational scanning of the protein residues and network modeling of epistatic interactions. This multifaceted computational study characterized molecular mechanisms and identified energetic hotspots that can mediate the predicted increased stability and the enhanced binding affinity of the BA.2.75 and XBB.1.5 complexes. The results suggested a mechanism driven by the stability hotspots and a spatially localized group of the Omicron binding affinity centers, while allowing for functionally beneficial neutral Omicron mutations in other binding interface positions. A network-based community model for the analysis of non-additive epistatic contributions in the Omicron complexes is proposed revealing the key role of the binding hotspots R498 and Y501 in mediating community-based epistatic couplings with other Omicron sites and allowing for compensatory dynamics and binding energetic changes. The results also showed that mutations in the convergent evolutionary hotspot F486 can modulate not only local interactions but also rewire the global network of local communities in this region allowing the F486P mutation to restore both the stability and binding affinity of the XBB.1.5 variant which may explain the growth advantages over the XBB.1 variant. The results of this study are consistent with a broad range of functional studies rationalizing functional roles of the Omicron mutation sites that form a coordinated network of hotspots enabling balance of multiple fitness tradeoffs and shaping up a complex functional landscape of virus transmissibility.

show abstract

Frustration-driven allosteric regulation and signal transmission in the SARS-CoV-2 spike omicron trimer structures: a crosstalk of the omicron mutation sites allosterically regulates tradeoffs of protein stability and conformational adaptability

Abstract: Dissecting the regulatory principles underlying function and activity of the SARS-CoV-2 spike protein at the atomic level is of paramount importance for the understanding mechanisms of virus transmissibility and immune...

Cited by 11 publications

References 117 publications

Molecular Investigations of Selected Spike Protein Mutations in SARS-CoV-2: Delta and Omicron Variants and Omicron Subvariants

Molecular Investigations of Selected Spike Protein Mutations in SARS-CoV-2: Delta and Omicron Variants and Omicron Subvariants

Exploring and Learning the Universe of Protein Allostery Using Artificial Intelligence Augmented Biophysical and Computational Approaches

Balancing Functional Tradeoffs between Protein Stability and ACE2 Binding in the SARS-CoV-2 Omicron BA.2, BA.2.75 and XBB Lineages : Dynamics-Based Network Models Reveal Epistatic Effects Modulating Compensatory Dynamic and Energetic Changes

Contact Info

Product

Resources

About