Molecular Simulations and Network Modeling Reveal an Allosteric Signaling in the SARS-CoV-2 Spike Proteins

Verkhivker, Gennady M.

doi:10.1021/acs.jproteome.0c00654

Cited by 77 publications

(125 citation statements)

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“…These results are consistent with our recent studies suggesting that closed and open prefusion forms of the SARS-CoV-2 spike trimer could become more dynamic than the “locked-closed” trimer conformations in which mobility of the NTD and RBD regions are largely suppressed. 64 …”

Section: Resultsmentioning

confidence: 99%

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Dynamic Network Modeling of Allosteric Interactions and Communication Pathways in the SARS-CoV-2 Spike Trimer Mutants: Differential Modulation of Conformational Landscapes and Signal Transmission via Cascades of Regulatory Switches

2021

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The rapidly growing body of structural and biochemical studies of the SARS-CoV-2 spike glycoprotein has revealed a variety of distinct functional states with radically different arrangements of the receptor-binding domain, highlighting a remarkable function-driven conformational plasticity and adaptability of the spike proteins. In this study, we examined molecular mechanisms underlying conformational and dynamic changes in the SARS-CoV-2 spike mutant trimers through the lens of dynamic analysis of allosteric interaction networks and atomistic modeling of signal transmission. Using an integrated approach that combined coarsegrained molecular simulations, protein stability analysis, and perturbation-based modeling of residue interaction networks, we examined how mutations in the regulatory regions of the SARS-CoV-2 spike protein can differentially affect dynamics and allosteric signaling in distinct functional states. The results of this study revealed key functional regions and regulatory centers that govern collective dynamics, allosteric interactions, and control signal transmission in the SARS-CoV-2 spike proteins. We found that the experimentally confirmed regulatory hotspots that dictate dynamic switching between conformational states of the SARS-CoV-2 spike protein correspond to the key hinge sites and global mediating centers of the allosteric interaction networks. The results of this study provide a novel insight into allosteric regulatory mechanisms of SARS-CoV-2 spike proteins showing that mutations at the key regulatory positions can differentially modulate distribution of states and determine topography of signal communication pathways operating through state-specific cascades of control switch points. This analysis provides a plausible strategy for allosteric probing of the conformational equilibrium and therapeutic intervention by targeting specific hotspots of allosteric interactions and communications in the SARS-CoV-2 spike proteins.

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Section: Resultsmentioning

confidence: 99%

“… 63 Molecular simulations and network modeling approaches were also used on our most recent investigation to present evidence that the SARS-CoV-2 spike protein can function as an allosteric regulatory engine that fluctuates between dynamically distinct functional states. 64 …”

Section: Introductionmentioning

confidence: 99%

Dynamic Network Modeling of Allosteric Interactions and Communication Pathways in the SARS-CoV-2 Spike Trimer Mutants: Differential Modulation of Conformational Landscapes and Signal Transmission via Cascades of Regulatory Switches

2021

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“…This extends beyond the scope of the present study and will be presented elsewhere. In this context, our most recent study of the SARS-CoV-2 spike trimers using perturbation analysis and network modeling presented evidence that the SARS-CoV-2 spike protein can function as an allosteric regulatory engine that fluctuates between dynamically distinct functional states [ 37 ].…”

Section: Resultsmentioning

confidence: 99%

“…The rapidly emerging plethora of computational studies examined SARS-CoV-2-RBD interactions with ACE2 enzyme using the recent crystal structures [ 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 ]. It was proposed that SARS-CoV-2-RBD may have adopted a specific strategy for achieving favorable binding affinity by exploiting the larger binding interface as compared to the SARS-CoV-RBD that employs the fewer contacts and could rely only on major hotpot centers [ 29 ].…”

Section: Introductionmentioning

confidence: 99%

“…MD simulations of the SARS-CoV-2 spike glycoprotein identified the changes in the molecular properties due to conformational flexibility [ 35 ]. Several computational methods were used to identify potential allosteric sites on the SARS-CoV-2 spike protein [ 36 ] and employed network modeling to suggest allosteric signaling as a possible mechanism underlying virus transmission in the SARS-CoV-2 spike proteins [ 37 ]. Although computational studies provided interesting insights into the molecular nature of the binding interactions, a clear consensus and quantitative understanding of the key determinants of the binding affinity and selectivity has not been reached.…”

Section: Introductionmentioning

confidence: 99%

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Coevolution, Dynamics and Allostery Conspire in Shaping Cooperative Binding and Signal Transmission of the SARS-CoV-2 Spike Protein with Human Angiotensin-Converting Enzyme 2

Verkhivker

2020

IJMS

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Binding to the host receptor is a critical initial step for the coronavirus SARS-CoV-2 spike protein to enter into target cells and trigger virus transmission. A detailed dynamic and energetic view of the binding mechanisms underlying virus entry is not fully understood and the consensus around the molecular origins behind binding preferences of SARS-CoV-2 for binding with the angiotensin-converting enzyme 2 (ACE2) host receptor is yet to be established. In this work, we performed a comprehensive computational investigation in which sequence analysis and modeling of coevolutionary networks are combined with atomistic molecular simulations and comparative binding free energy analysis of the SARS-CoV and SARS-CoV-2 spike protein receptor binding domains with the ACE2 host receptor. Different from other computational studies, we systematically examine the molecular and energetic determinants of the binding mechanisms between SARS-CoV-2 and ACE2 proteins through the lens of coevolution, conformational dynamics, and allosteric interactions that conspire to drive binding interactions and signal transmission. Conformational dynamics analysis revealed the important differences in mobility of the binding interfaces for the SARS-CoV-2 spike protein that are not confined to several binding hotspots, but instead are broadly distributed across many interface residues. Through coevolutionary network analysis and dynamics-based alanine scanning, we established linkages between the binding energy hotspots and potential regulators and carriers of signal communication in the virus–host receptor complexes. The results of this study detailed a binding mechanism in which the energetics of the SARS-CoV-2 association with ACE2 may be determined by cumulative changes of a number of residues distributed across the entire binding interface. The central findings of this study are consistent with structural and biochemical data and highlight drug discovery challenges of inhibiting large and adaptive protein–protein interfaces responsible for virus entry and infection transmission.

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Probing structural basis for enhanced binding of SARS‐CoV‐2 P.1 variant spike protein with the human ACE2 receptor

Lata

Akif

2022

J of Cellular Biochemistry

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The initial step of infection by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) involves the binding of receptor binding domain (RBD) of the spike protein to the angiotensin converting enzyme 2 (ACE2) receptor. Each successive wave of SARS‐CoV‐2 reports emergence of many new variants, which is associated with mutations in the RBD as well as other parts of the spike protein. These mutations are reported to have enhanced affinity towards the ACE2 receptor as well as are also crucial for the virus transmission. Many computational and experimental studies have demonstrated the effect of individual mutation on the RBD‐ACE2 binding. However, the cumulative effect of mutations on the RBD and away from the RBD was not investigated in detail. We report here a comparative analysis on the structural communication and dynamics of the RBD and truncated S1 domain of spike protein in complex with the ACE2 receptor from SARS‐CoV‐2 wild type and its P.1 variant. Our integrative network and dynamics approaches highlighted a subtle conformational changes in the RBD as well as truncated S1 domain of spike protein at the protein contact level, responsible for the increased affinity with the ACE2 receptor. Moreover, our study also identified the commonalities and differences in the dynamics of the interactions between spike protein of SARS‐CoV‐2 wild type and its P.1 variant with the ACE2 receptor. Further, our investigation yielded an understanding towards identification of the unique RBD residues crucial for the interaction with the ACE2 host receptor. Overall, the study provides an insight for designing better therapeutics against the circulating P.1 variants as well as other future variants.

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Molecular Simulations and Network Modeling Reveal an Allosteric Signaling in the SARS-CoV-2 Spike Proteins

Cited by 77 publications

References 125 publications

Dynamic Network Modeling of Allosteric Interactions and Communication Pathways in the SARS-CoV-2 Spike Trimer Mutants: Differential Modulation of Conformational Landscapes and Signal Transmission via Cascades of Regulatory Switches

Dynamic Network Modeling of Allosteric Interactions and Communication Pathways in the SARS-CoV-2 Spike Trimer Mutants: Differential Modulation of Conformational Landscapes and Signal Transmission via Cascades of Regulatory Switches

Coevolution, Dynamics and Allostery Conspire in Shaping Cooperative Binding and Signal Transmission of the SARS-CoV-2 Spike Protein with Human Angiotensin-Converting Enzyme 2

Probing structural basis for enhanced binding of SARS‐CoV‐2 P.1 variant spike protein with the human ACE2 receptor

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