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.

Gennady Verkhivker

doi:10.3390/ijms21218268

Abstract

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.

Highlights

The coronavirus disease 2019 (COVID-19) pandemic has emerged as a global international health crisis that has spread over the world with far-reaching implications for global economy, peace, and security [1,2]
The results of this study show that despite structural similarities between spike proteins, severe acute respiratory syndrome (SARS)-CoV-2-receptor-binding domain (RBD) can act as plastic and versatile modulator of virus entry in which dynamic interactions with angiotensin-converting enzyme 2 (ACE2) can be mediated through a non-trivial interplay of recognition energy hotspots and broad binding interfaces
The sequence conservation of S1 RBD yielded ≈73% identity, while the receptor binding motif (RBM) region involved in direct interactions with the ACE2 receptor displayed a more significant variability as similarity between SARS-CoV and SARS-CoV-2 sequences dropped to ≈50% (Figure 2)

Summary

Introduction

The coronavirus disease 2019 (COVID-19) pandemic has emerged as a global international health crisis that has spread over the world with far-reaching implications for global economy, peace, and security [1,2]. SARS-CoV-2 binds to the ACE2 receptor on the surface of the host cell using binding of the S1 region of the virus spike (S) protein followed by the fusion of the viral and cellular membranes mediated by the S2 subunit of the spike S protein [13]. The crystal structures of the SARS-CoV-RBD [21,22,23] and SARS-CoV-2-RBD proteins bound to the host receptor ACE2 [24] (Figure 1) provided a foundation for understanding dynamic and energetic differences between these spike proteins These studies reported a high degree of structural similarity between SARS-CoV-RBD and SARS-CoV-2-RBD proteins with a root mean square deviation, RMSD = 1.2 Å for Cα atoms, and even a lower RMSD = 0.68 Å between ACE2 conformations, indicating that the structural arrangement of the binding interfaces in the SARS-CoV-RBD and SARS-CoV-2-RBD complexes with ACE2 is virtually identical [24]. Sequence analysis revealed a considerable similarity between SARS-CoV-2 and SARS-CoV RBD proteins (Figure 2), suggesting convergent evolution of spike structural folds for binding to ACE2 enzyme [21,24]

Methods

Results

Conclusion