| Popis: |
In the current study, we combine multiple microsecond MD simulations and Markov state models (MSM) to characterize conformational landscapes and identify specific dynamic signatures of the SARS-CoV-2 S RBD-ACE2 complexes for the recently emerged XBB.1, XBB.1.5, BQ.1, and BQ.1.1 Omicron variants. Despite considerable structural similarities in the RBD-ACE2 complexes, Omicron mutations induce unique dynamic signatures and specific distributions of conformational states that explain the patterns of stability and immune escape in the Omicron variants. Microsecond atomistic simulations and MSM analysis provide a detailed characterization of the conformational landscapes and reveal the increased thermodynamic stabilization of the XBB.1.5 subvariant which is contrasted to more dynamic BQ.1 and BQ.1.1 subvariants. Using a comparative MSM analysis we show that the distribution of dominant macrostates in the Omicron variants can allow for allosteric modulation of mobility in the flexible RBD loops 470-491 and 440-452 involved in the interfacial contacts and containing critical convergent mutation sites. Our results suggest that variant-specific changes of conformational mobility in these functional loops can be fine-tuned through cross-talk between convergent mutations thereby providing an evolutionary path for the improved immune escape without significant cost on the ACE2 binding. By combining MD simulations and MSM analysis with perturbation-based response scanning approaches, we also examine mechanisms of long-range dynamic couplings and allosteric communications in the Omicron RBD-ACE2 complexes. Based on premise that allostery is linked with the evolvability of proteins, we explore the relationship between allosteric interactions and patterns of convergent Omicron mutations, showing how convergent mutations can potentiate conformational plasticity and modulate allosteric responses in the RBD to binding and immune escape. Through perturbation response scanning analysis, our study reveals important complementary roles of convergent mutation sites as effectors/regulators and sensors/receivers of S-RBD plasticity allosteric signal transmission in the RBD-ACE2 complexes. By using fast and accurate allosteric site prediction PASSer (Protein Allosteric Sites Server) we characterize the effect of dynamics on the distribution of allosteric pockets in the Omicron subvariants. The results show that variant-specific redistribution of macrostates preserves the experimentally known allosteric pocket on the RBD while allowing for the emergence of hidden allosteric pockets that are anchored by convergent mutation sites K444T and L452R. Through integrative computational approaches, this study provides a systematic analysis and comparison of the effects of Omicron subvariants on conformational dynamics, binding and allosteric signaling in the complexes with the ACE2 receptor. |
