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

Abstract

The development of computational strategies for the quantitative characterization of the functional mechanisms of SARS-CoV-2 spike proteins is of paramount importance in efforts to accelerate the discovery of novel therapeutic agents and vaccines combating the COVID-19 pandemic. Structural and biophysical studies have recently characterized the conformational landscapes of the SARS-CoV-2 spike glycoproteins in the prefusion form, revealing a spectrum of stable and more dynamic states. By employing molecular simulations and network modeling approaches, this study systematically examined functional dynamics and identified the regulatory centers of allosteric interactions for distinct functional states of the wild-type and mutant variants of the SARS-CoV-2 prefusion spike trimer. This study presents evidence that the SARS-CoV-2 spike protein can function as an allosteric regulatory engine that fluctuates between dynamically distinct functional states. Perturbation-based modeling of the interaction networks revealed a key role of the cross-talk between the effector hotspots in the receptor binding domain and the fusion peptide proximal region of the SARS-CoV-2 spike protein. The results have shown that the allosteric hotspots of the interaction networks in the SARS-CoV-2 spike protein can control the dynamic switching between functional conformational states that are associated with virus entry to the host receptor. This study offers a useful and novel perspective on the underlying mechanisms of the SARS-CoV-2 spike protein through the lens of allosteric signaling as a regulatory apparatus of virus transmission that could open up opportunities for targeted allosteric drug discovery against SARS-CoV-2 proteins and contribute to the rapid response to the current and potential future pandemic scenarios.

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

“…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 …”

“… 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 …”

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

“…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 ].…”

“…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 ].…”

“…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.…”