Molecular dynamics simulations highlight the altered binding landscape at the spike-ACE2 interface between the Delta and Omicron variants compared to the SARS-CoV-2 original strain

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) B.1.1.529 variant (Omicron), represents a significant deviation in genetic makeup and function compared to previous variants. Following the BA.1 sublineage, the BA.2 and BA.3 Omicron subvariants became dominant, and currently the BA.4 and BA.5, which are quite distinct variants, have emerged. Using molecular dynamics simulations, we investigated the binding characteristics of the Delta and Omicron (BA.1) variants in comparison to wild-type (WT) at the interface of the spike protein receptor binding domain (RBD) and human angiotensin converting enzyme-2 (ACE2) ectodomain. The primary aim was to compare our molecular modelling systems with previously published observations, to determine the robustness of our approach for rapid prediction of emerging future variants. Delta and Omicron were found to bind to ACE2 with similar affinities (-39.4 and -43.3 kcal/mol, respectively) and stronger than WT (-33.5 kcal/mol). In line with previously published observations, the energy contributions of the non-mutated residues at the interface were largely retained between WT and the variants, with F456, F486, and Y489 having the strongest energy contributions to ACE2 binding. Further, residues N440K, Q498R, and N501Y were predicted to be energetically favourable in Omicron. In contrast to Omicron, which had the E484A and K417N mutations, intermolecular bonds were detected for the residue pairs E484:K31 and K417:D30 in WT and Delta, in accordance with previously published findings. Overall, our simplified molecular modelling approach represents a step towards predictive model systems for rapidly analysing arising variants of concern.

Keywords: ACE2 receptors; Delta variant; Omicron variant; SARS-CoV-2; Spike protein.

Graphical abstract

Fig. 1

Structures of the Delta and Omicron SARS-CoV-2 variants. The cryo-EM structure of the wild-type (WT) full-length trimeric spike protein (PDB ID: 7A98) was mutated to generate the Delta (A) and Omicron variants (B). The mutated residues for the Delta and Omicron variants are labelled for chain A and are shown in orange and brown, respectively. The receptor binding domain (RBD) mutations are highlighted.

Fig. 2

Classical molecular dynamics (MD) simulation of SARS-CoV-2 variant spike receptor binding domains (RBD) bound to human angiotensin converting enzyme-2 (ACE2). SARS-CoV-2 variant spike RBDs examined were wild-type (grey), Delta (blue), and Omicron (yellow). Simulations were performed for 100 ns in triplicate. Data is shown for the RBD protein backbone as the average of triplicate runs, with data shown every 100 ps for all time series plots. (A) Average root mean square deviation (RMSD) with respect to its initial structure. (B) Radius of gyration. (C) Principal component analysis of protein motion along the first two eigenvectors. Trajectories were concatenated following equilibration. (D) Solvent accessible surface area. (E) Number of hydrogen bonds between variant spike RBDs and human ACE2 throughout the simulation.

Fig. 3

Root mean square fluctuation (RMSF) analysis of SARS-CoV-2 variant spike receptor binding domains (RBD) bound to human angiotensin converting enzyme-2 (ACE2). Variant spike RBDs examined were wild-type (WT) (grey), Delta (blue), and Omicron (yellow). (A) Average (RMSF) of the RBD protein backbone. (B) 3D representation of WT spike RBD to illustrate secondary structure. (C) Difference in RMSF for variant spike RBDs following subtraction of WT values. Mutations labelled are present in the Omicron variant, with the exception of L452R (*) found in the Delta variant only, and T478K (**) present in both Delta and Omicron variants. (D) 3D representation of WT spike RBD to illustrate secondary structure. For 3D representations, the protein is represented as ribbons. Individual residues are highlighted in van der Waals representation, and regions of residues are shown as sticks. Colours indicate secondary structure: alpha helices (purple), extended beta sheets (yellow), turn (cyan), beta bridge (tan), and coil (white).

Fig. 4

Cluster analysis of SARS-CoV-2 variant spike receptor binding domains (RBDs) bound to human angiotensin converting enzyme-2 (ACE2). Analysis was performed on the RBD protein backbone using a root mean square deviation (RMSD) cut-off of 0.10 nm to define structures within each cluster. The cluster number over time throughout concatenated triplicate trajectories is represented as a heat map for 27,000 frames (left), with the six most prevalent clusters shown in colours indicated by the legend. Frames assigned to clusters seven and beyond are shown in black. The top three clusters for each system are depicted schematically (right), with the proportion of frames assigned to each cluster indicated as a percentage.

Fig. 5

Structures of the wild-type (WT) SARS-CoV-2 spike protein. The WT full-length trimeric spike protein (PDB ID: 7A98) is depicted with chains A, B and C coloured blue, yellow, and grey, respectively (A). The crystal structure of the spike protein receptor binding domain (RBD) in complex with the human angiotensin converting enzyme-2 (ACE2) receptor (PDB ID: 6M0J) can be seen. The key RBD:ACE2 ectodomain interface residues are labelled, with the italicised residues located on the ACE2 protein (B). For reference, experimental affinity constants (K_D) for the variants are shown, highlighting binding in the low nanomolar range.

Fig. 6

Key residues at the interface of the wild-type (WT), Delta and Omicron variant receptor binding domain (RBD) complexes with human angiotensin receptor-2 (ACE2). The representative RBD:ACE2 ectodomain structures of the WT (A), Delta (B), and Omicron (C) variants from the top three clusters are shown (clusters correspond to those defined in Fig. 4). The hydrogen bonds and salt bridges that the RBD residues were predicted to form with the ACE2 ectodomain are highlighted. The mutated residues in the Delta and Omicron RBDs are marked with an asterisk (*).

Fig. 7

Energy contribution of residues at the receptor binding domain (RBD) and human angiotensin converting enzyme-2 (ACE2) ectodomain interface. The contribution of key interface residues to binding between wild-type (WT), Delta and Omicron variants and ACE2 are shown. Binding energy estimated by pyDock was decomposed on a per-residue basis, with contributions shown for RBD interface residues (A) and mutations characteristic of the variants (B). In terms of energy contribution differential, residue 498 appears to be the most critical, with the mutation of glutamine to arginine favouring binding of the Delta and Omicron variants compared to WT. Mutations shown are found in the Omicron variant, with the exception of L452R (*) found in the Delta variant only, and T478K (**) present in both Delta and Omicron variants.

Fig. 8

Minimum distance between selected residue pairs at the SARS-CoV-2 spike protein receptor binding domain and human angiotensin converting enzyme-2 (RBD:ACE2) interface. Distance with respect to simulation time is shown for WT (grey), Delta (blue), and Omicron (yellow) variants. In each case, the residues pairs are highlighted in figures (A–F). Data is plotted in increments of 0.5 ns; the average of three independent production runs for each system is depicted.