Computer Simulations and Network-Based Profiling of Binding and Allosteric Interactions of SARS-CoV-2 Spike Variant Complexes and the Host Receptor: Dissecting the Mechanistic Effects of the Delta and Omicron Mutations

Abstract

In this study, we combine all-atom MD simulations and comprehensive mutational scanning of S-RBD complexes with the angiotensin-converting enzyme 2 (ACE2) host receptor in the native form as well as the S-RBD Delta and Omicron variants to (a) examine the differences in the dynamic signatures of the S-RBD complexes and (b) identify the critical binding hotspots and sensitivity of the mutational positions. We also examined the differences in allosteric interactions and communications in the S-RBD complexes for the Delta and Omicron variants. Through the perturbation-based scanning of the allosteric propensities of the SARS-CoV-2 S-RBD residues and dynamics-based network centrality and community analyses, we characterize the global mediating centers in the complexes and the nature of local stabilizing communities. We show that a constellation of mutational sites (G496S, Q498R, N501Y and Y505H) correspond to key binding energy hotspots and also contribute decisively to the key interfacial communities that mediate allosteric communications between S-RBD and ACE2. These Omicron mutations are responsible for both favorable local binding interactions and long-range allosteric interactions, providing key functional centers that mediate the high transmissibility of the virus. At the same time, our results show that other mutational sites could provide a “flexible shield” surrounding the stable community network, thereby allowing the Omicron virus to modulate immune evasion at different epitopes, while protecting the integrity of binding and allosteric interactions in the RBD–ACE2 complexes. This study suggests that the SARS-CoV-2 S protein may exploit the plasticity of the RBD to generate escape mutants, while engaging a small group of functional hotspots to mediate efficient local binding interactions and long-range allosteric communications with ACE2.

Probing Mechanisms of Binding and Allostery in the SARS-CoV-2 Spike Omicron Variant Complexes with the Host Receptor: Revealing Functional Roles of the Binding Hotspots in Mediating Epistatic Effects and Communication with Allosteric Pockets

“…The conformational mobility distributions for the Omicron RBD complexes displayed several deep local minima corresponding to residues 374–377 and the RBD core residue cluster (residues 396–403) as well as interfacial RBD positions that are involved in the contacts with the hACE2 receptor (residues 445–456 and 496–505 of the binding interface) ( Figure 2 A). The observed structural stability of the core RBD regions was also seen in our earlier simulation studies of the original RBD Wu-Hu-1 and Omicron complexes [ 64 ], indicating that these segments remain relatively rigid in all Omicron variant complexes with hACE2. Noteworthy, the most stable RBD positions included important hydrophobic stability centers F400, I402, F490, Y453, L455, A475, and Y489 ( Figure 2 A).…”

“…The study concluded that Omicron BA.2 subvariant may have evolved to maintain ACE2 binding similar to the original strain while promoting more efficient antibody evasion highlighting how a complex pattern of mutations balances these conflicting factors [ 63 ]. By employing the conformational ensembles of the S-RBD Omicron variant complexes with ACE2 we recently performed simulations and mutational scanning of the interfacial RBD residues showing that N501Y is the critical binding affinity hotspot in the S Omicron RBD complex with ACE2, while hotspots Q493R, G496S, Q498R anchor the key interfacial clusters responsible for binding with ACE2 [ 64 ]. By assessing over 700 mutant complexes, the recent study revealed that high-affinity RBD mutations (including N440K, S443A, G476S, E484R, G502P) tend to cluster near known human ACE2 recognition sites supporting the view that combinatorial mutations in SARS-CoV-2 can develop in sites amenable for non-additive enhancements in binding and antibody evasion.…”

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

“…The conformational mobility distributions for the Omicron RBD complexes displayed several deep local minima corresponding to residues 374-377 and the RBD core residue cluster (residues 396-403) as well as interfacial RBD positions that are involved in the contacts with the hACE2 receptor (residues 445-456 and 496-505 of the binding interface) (Figure 2A). The observed structural stability of the core RBD regions was also seen in our earlier simulation studies of the original RBD Wu-Hu-1 and Omicron complexes [65], indicating that these segments remain relatively rigid in all Omicron variant complexes with hACE2. Noteworthy, the most stable RBD positions included important hydrophobic stability centers F400, I402, F490, Y453, L455, A475, and Y489 (Figure 2A).…”

“…The study concluded that Omicron BA.2 subvariant may have evolved to maintain ACE2 binding similar to the original strain while promoting more efficient antibody evasion highlighting how complex pattern of mutations balances these conflicting factors [64]. By employing the conformational ensembles of the S-RBD Omicron variant complexes with ACE2 we recently performed simulations and mutational scanning of the interfacial RBD residues showing that N501Y is the critical binding affinity hotspot in the S Omicron RBD complex with ACE2, while hotspots Q493R, G496S, Q498R anchor the key interfacial clusters responsible for binding with ACE2 [65]. By assessing over 700 mutant complexes, the recent study revealed that high-affinity RBD mutations (including N440K, S443A, G476S, E484R, G502P) tend to cluster near known human ACE2 recognition sites supporting the view that combinatorial mutations in SARS-CoV-2 can develop in sites amenable for non-additive enhancements in binding and antibody evasion.…”

Integrating Conformational Dynamics and Perturbation-Based Network Modeling for Mutational Profiling of Binding and Allostery in the SARS-CoV-2 Spike Variant Complexes with Antibodies: Balancing Local and Global Determinants of Mutational Escape Mechanisms

“…The effect of nonadditive, epistatic relationships among RBD mutations was assessed using protein structure modeling by comparing the effects of all single mutants at the RBD–ACE2 interfaces for the Omicron variants, showing that structural constraints on the RBD can curtail the virus evolution for a more complete vaccine and antibody escape [ 78 ]. By employing the conformational ensembles of the S-RBD Omicron variant complexes with ACE2, we recently performed simulations and mutational scanning of the interfacial RBD residues, showing that N501Y is the critical binding affinity hotspot in the S Omicron RBD complex with ACE2, while hotspots Q493R, G496S, and Q498R anchor the key interfacial clusters responsible for binding with ACE2 [ 79 ].…”