Probing Conformational Landscapes of Binding and Allostery in the SARS-CoV-2 Omicron Variant Complexes Using Microsecond Atomistic Simulations and Perturbation-Based Profiling Approaches: Hidden Role of Omicron Mutations as Modulators of Allosteric Signaling and Epistatic Relationships

Abstract

In this study, we systematically examine the conformational dynamics, binding and allosteric communications in the Omicron BA.1, BA.2, BA.3 and BA.4/BA.5 complexes with the ACE2 host receptor using molecular dynamics simulations and perturbation-based network profiling approaches. Microsecond atomistic simulations provided a detailed characterization of the conformational landscapes and revealed the increased thermodynamic stabilization of the BA.2 variant which is contrasted with the BA.4/BA.5 variants inducing a significant mobility of the complexes. Using ensemble-based mutational scanning of binding interactions, we identified binding affinity and structural stability hotspots in the Omicron complexes. Perturbation response scanning and network-based mutational profiling approaches probed the effect of the Omicron variants on allosteric communications. The results of this analysis revealed specific roles of Omicron mutations as plastic and evolutionary adaptable modulators of binding and allostery which are coupled to the major regulatory positions through interaction networks. Through perturbation network scanning of allosteric residue potentials in the Omicron variant complexes, which is performed in the background of the original strain, we identified that the key Omicron binding affinity hotspots N501Y and Q498R could mediate allosteric interactions and epistatic couplings. Our results suggested that the synergistic role of these hotspots in controlling stability, binding and allostery can enable for compensatory balance of fitness tradeoffs with conformationally and evolutionary adaptable immune-escape Omicron mutations. Through integrative computational approaches, this study provides a systematic analysis of the effects of Omicron mutations on thermodynamics, binding and allosteric signaling in the complexes with ACE2 receptor. The findings support a mechanism in which Omicron mutations can evolve to balance thermodynamic stability and conformational adaptability in order to ensure proper tradeoff between stability, binding and immune escape.

Accurate Characterization of Conformational Ensembles and Binding Mechanisms of the SARS-CoV-2 Omicron BA.2 and BA.2.86 Spike Protein with the Host Receptor and Distinct Classes of Antibodies Using AlphaFold2-Augmented Integrative Computational Modeling

“…[120][121][122] These predictions may be relevant for the BA.2.86 RBD dynamic responses to binding in which variant-specific mutations may increase adaptability of the RBD loop and exploit the induced plasticity to boost immune evasion. The AF2 predictions are also consistent with our previous MD simulation studies of the Omicron RBD-ACE2 complexes, showing that the major structural differences between Omicron BQ.1 and XBB.1/XBB.1.5 RBD-ACE2 complexes are mostly confined to the fluctuations of the flexible loop regions 444-452 and 475-487 70,71 .…”

“…63,64 Our recent studies demonstrated that Omicron mutational sites can be dynamically coupled forming an adaptive allosteric network that controls balance and tradeoffs between conformational plasticity, protein stability, and functional adaptability. 65--69 We combined MD simulations and Markov state models to systematically characterize conformational landscapes and identify specific dynamic signatures of the early Omicron variants BA.1, BA.2, BA.3 and BA.4/BA.5 variants 70 and recent highly transmissible XBB.1, XBB.1.5, BQ.1, and BQ.1.1 Omicron variants and their complexes. 71 A significant number of computational studies emphasized the role of electrostatic interactions as a dominant thermodynamic force leading at binding of the S-protein with the ACE2 receptor and antibodies.…”

The accomplices: Heparan sulfates and N-glycans foster SARS-CoV-2 spike:ACE2 receptor binding and virus priming

“…S7). Notably, Verkhivker and co-workers (Verkhivker et al, 2023) identified a negative cross-correlated movement of these residues in the newer omicron spike variants upon ACE2 binding in the absence of heparin, while Kim and colleagues (Kim et al, 2023) showed that omicron spike interactions with HS and ACE2 are significantly enhanced compared to the Wuhan variant. Consistent with these and our findings, newer omicron spike variants could require HS to stabilize the protein:protein interface for subsequent steps in the infection process.…”

Predicting Functional Conformational Ensembles and Binding Mechanisms of Convergent Evolution for SARS-CoV-2 Spike Omicron Variants Using AlphaFold2 Sequence Scanning Adaptations and Molecular Dynamics Simulations

“…61 Integrative computational modeling approaches revealed that the S protein could function as an allosteric regulatory machinery controlled by stable allosteric hotspots acting as drives drivers and regulators of spike activity. [62][63][64][65][66][67] By combining atomistic simulations and a community-based network model of epistatic couplings we found that convergent Omicron mutations can display epistatic relationships with the major stability and binding affinity hotspots which may allow for the observed broad antibody resistance. 65 Analysis of conformational dynamics and allosteric communications in the Omicron BA.1, BA.2, BA.3 and BA.4/BA.5 complexes with the ACE2 host receptor characterized regions of epistatic couplings that are centered at the binding affinity hotspots N501Y and Q498R enabling accumulation of multiple Omicron immune escape mutations at other sites.…”

“…65 Analysis of conformational dynamics and allosteric communications in the Omicron BA.1, BA.2, BA.3 and BA.4/BA.5 complexes with the ACE2 host receptor characterized regions of epistatic couplings that are centered at the binding affinity hotspots N501Y and Q498R enabling accumulation of multiple Omicron immune escape mutations at other sites. 66 MD simulations and Markov state models systematically characterized conformational landscapes and identify specific dynamic signatures of Omicron variants and their complexes showing that convergent mutation sites could control evolution allosteric pockets through modulation of conformational plasticity in the flexible adaptable regions. 67 Recent computational studies suggested that Omicron mutations have variant-specific effect on conformational dynamics changes in the S protein including allosterically induced plasticity at the remote regions leading to the formation and evolution of druggable cryptic pockets.…”