Some mechanistic underpinnings of molecular adaptations of SARS-COV-2 spike protein by integrating candidate adaptive polymorphisms with protein dynamics

Abstract

We integrate evolutionary predictions based on the neutral theory of molecular evolution with protein dynamics to generate mechanistic insight into the molecular adaptations of the SARS-COV-2 Spike (S) protein. With this approach, we first identified Candidate Adaptive Polymorphisms (CAPs) of the SARS-CoV-2 Spike protein and assessed the impact of these CAPs through dynamics analysis. Not only have we found that CAPs frequently overlap with well-known functional sites, but also, using several different dynamics-based metrics, we reveal the critical allosteric interplay between SARS-CoV-2 CAPs and the S protein binding sites with the human ACE2 (hACE2) protein. CAPs interact far differently with the hACE2 binding site residues in the open conformation of S protein compared to the closed form. In particular, the CAP sites control the dynamics binding residues in the open state, suggesting an allosteric control of hACE2 binding. We also explored the characteristic mutations of different SARS-CoV-2 strains to find dynamic hallmarks and potential effects of future mutations. Our analyses reveal that Delta strain-specific variants have non-additive (i.e., epistatic) interactions with CAP sites, whereas the less pathogenic Omicron strains have mostly compensatory variants. Finally, our dynamics-based analysis suggests that the novel mutations observed in the Omicron strain epistatically interact with the CAP sites to help escape antibody binding.

Atomistic Prediction of Structures, Conformational Ensembles and Binding Energetics for the SARS-CoV-2 Spike JN.1, KP.2 and KP.3 Variants Using AlphaFold2 and Molecular Dynamics Simulations: Mutational Profiling and Binding Free Energy Analysis Reveal Epistatic Hotspots of the ACE2 Affinity and Immune Escape

“…The results of this study provided molecular rationale and support to the experimental evidence that functionally balanced substitutions that optimize tradeoffs between immune evasion, high ACE2 affinity and sufficient conformational adaptability might be a common strategy of the virus evolution and serve as a primary driving force behind the emergence of new Omicron subvariants, including but not limited to BA. showing that Omicron variants can induce distinct dynamics and exploit epistatic interactions between sites R346, F486P, Q498, Q493 to modulate the RBD-ACE2 interface with increasing flexibility in antibody binding residues [118]. The results also demonstrated that L455, F456 and 58 Q493 are pronounced escape hotspots of resistance to class I antibodies.…”