Coordinated evolution at amino acid sites of SARS-CoV-2 spike

Abstract

SARS-CoV-2 has adapted in a stepwise manner, with multiple beneficial mutations accumulating in a rapid succession at origins of VOCs, and the reasons for this are unclear. Here, we searched for coordinated evolution of amino acid sites in the spike protein of SARS-CoV-2. Specifically, we searched for concordantly evolving site pairs (CSPs) for which changes at one site were rapidly followed by changes at the other site in the same lineage. We detected 46 sites which formed 45 CSP. Sites in CSP were closer to each other in the protein structure than random pairs, indicating that concordant evolution has a functional basis. Notably, site pairs carrying lineage defining mutations of the four VOCs that circulated before May 2021 are enriched in CSPs. For the Alpha VOC, the enrichment is detected even if Alpha sequences are removed from analysis, indicating that VOC origin could have been facilitated by positive epistasis. Additionally, we detected nine discordantly evolving pairs of sites where mutations at one site unexpectedly rarely occurred on the background of a specific allele at another site, for example on the background of wild-type D at site 614 (four pairs) or derived Y at site 501 (three pairs). Our findings hint that positive epistasis between accumulating mutations could have delayed the assembly of advantageous combinations of mutations comprising at least some of the VOCs.

AlphaFold2-Enabled Atomistic Modeling of Structure, Conformational Ensembles, and Binding Energetics of the SARS-CoV-2 Omicron BA.2.86 Spike Protein with ACE2 Host Receptor and Antibodies: Compensatory Functional Effects of Binding Hotspots in Modulating Mechanisms of Receptor Binding and Immune Escape

“…The results suggest that the BA.2.86 variant may have evolved to accumulate convergent immune escape mutations while exploiting potential synergistic epistatic effects of a selected group of hotspots R403K and R493Q to enable sufficient ACE2-binding capability. Several lines of evidence indicated that the observed coordination of evolution at different sites can be due to epistatic, rather than random selection of mutations. , …”

“…Several lines of evidence indicated that the observed coordination of evolution at different sites can be due to epistatic, rather than random selection of mutations. 124,125 MM-GBSA Computations of the Binding Free Energies for the Omicron RBD BA.2 and BA.2.86 RBD-ACE2 Complexes. Using the conformational equilibrium ensembles obtained from MD simulations, we computed the binding free energies for the Omicron RBD BA.2 and BA.2.86 RBD complexes with ACE2 using the MM-GBSA method.…”

Balancing Functional Tradeoffs between Protein Stability and ACE2 Binding in the SARS-CoV-2 Omicron BA.2, BA.2.75 and XBB Lineages : Dynamics-Based Network Models Reveal Epistatic Effects Modulating Compensatory Dynamic and Energetic Changes

“…Remarkably, convergent evolution seen in these examples allowed for the improved or neutral binding affinity changes and immune escape. Several lines of evidence indicated that the observed coordination of evolution at different sites is largely due to epistatic, rather than random selection of mutations [140]. Epistatic interactions between mutations add substantial complexity of their adaptive landscapes are believed to play an important role in the virus evolution.…”

Community structure and temporal dynamics of SARS-CoV-2 epistatic network allow for early detection of emerging variants with altered phenotypes

“…Notably, all predictions were made before the actual Omicron haplotypes emerged, at a cumulative frequency of 0. The Delta variant (B.1.617.2) serves as another example of multiple early predictions, as it becomes significantly dense in ten countries (F D des ∈ [15, 360] and F D prev ∈ [30,375]).…”