Molecular characterization of interactions between the D614G variant of SARS-CoV-2 S-protein and neutralizing antibodies: A computational approach

Abstract

The D614G variant of SARS-CoV-2 S-protein emerged in early 2020 and quickly became the dominant circulating strain in Europe and its environs. The variant was characterized by the higher viral load, which is not associated with disease severity, higher incorporation into the virion, and high cell entry via ACE-2 and TMPRSS2. Previous strains of the coronavirus and the current SARS-CoV-2 have demonstrated the selection of mutations as a mechanism of escaping immune responses. In this study, we used molecular dynamics simulation and MM-PBSA binding energy analysis to provide insights into the behaviour of the D614G S-protein at the molecular level and describe the neutralization mechanism of this variant. Our results show that the D614G S-protein adopts distinct conformational dynamics which is skewed towards the open-state conformation more than the closed-state conformation of the wild-type S-protein. Residue-specific variation of amino acid flexibility and domain-specific RMSD suggest that the mutation causes an allosteric conformational change in the RBD. Evaluation of the interaction energies between the S-protein and neutralizing antibodies show that the mutation may enhance, reduce or not affect the neutralizing interactions depending on the neutralizing antibody, especially if it targets the RBD. The results of this study have shed insights into the behaviour of the D614G S-protein at the molecular level and provided a glimpse of the neutralization mechanism of this variant.

Keywords: D614G; Molecular dynamics simulation; Neutralizing antibody; S-protein; SARS-CoV-2.

Fig. 1

Modeling of the SARS-CoV-2 S-protein. The distinct states of the S-protein were modeled based on their respective templates. Structural superposition of the (a) closed state to its template and (b) closed state to its template and their respective RMSD are show. (c) shows the distance the upward and downward orientation of the RBD. (d) shows the conservation profile of D614 of the S-protein.

Fig. 2

Backbone-RMSD values as a function of time. (a) RMSD plot of the wild-type, D614G and open-state S-proteins. The domain-specific RMSD profiles of the (b) NTD (c) RBD and (d) S2-domain are also shown.

Fig. 3

RMSF profile of the protein residues during the simulation. The plot shows the residue-specific variations in amino acid flexibility and movement during the simulation. Most affected regions of the S-protein with respect to RMSF variations are shown.

Fig. 4

Molecular view of the protein structures. (a) Snapshots of the structural conformations of the protein systems at different time points of the simulation. The RBD and the NTD are highlighted in red and green, respectively. (b) Conformation of the RBD in the wild-type, D614G and open-state S-proteins. The middle structure of the most populated cluster group for each protein was used for structural superposition.

Fig. 5

Classification of SARS-CoV-2 neutralizing antibodies. The neutralizing antibodies are grouped on the basis of their mechanism of neutralization and the domain of binding.

Fig. 6

MM-PBSA binding energy of the complexes.

Fig. 7

Energy contributions of S-protein residues during interactions with neutralizing antibodies. Residual energy contributions to interaction between the wild-type or D614G S-protein with (a) CB6 (b) P2B-2F6 (c) 4A8 are shown.

Fig. 8

The mapping of residue energy contribution on the the CB6 interaction interface. The energy contributions are in kJ/mol. The contribution of each residue is shown in colors as represented on the color scale.