Structural evolution of Delta lineage of SARS-CoV-2

Abstract

One of the main obstacles in prevention and treatment of COVID-19 is the rapid evolution of the SARS-CoV-2 Spike protein. Given that Spike is the main target of common treatments of COVID-19, mutations occurring at this virulent factor can affect the effectiveness of treatments. The B.1.617.2 lineage of SARS-CoV-2, being characterized by many Spike mutations inside and outside of its receptor-binding domain (RBD), shows high infectivity and relative resistance to existing cures. Here, utilizing a wide range of computational biology approaches, such as immunoinformatics, molecular dynamics (MD), analysis of intrinsically disordered regions (IDRs), protein-protein interaction analyses, residue scanning, and free energy calculations, we examine the structural and biological attributes of the B.1.617.2 Spike protein. Furthermore, the antibody design protocol of Rosetta was implemented for evaluation the stability and affinity improvement of the Bamlanivimab (LY-CoV55) antibody, which is not capable of interactions with the B.1.617.2 Spike. We observed that the detected mutations in the Spike of the B1.617.2 variant of concern can cause extensive structural changes compatible with the described variation in immunogenicity, secondary and tertiary structure, oligomerization potency, Furin cleavability, and drug targetability. Compared to the Spike of Wuhan lineage, the B.1.617.2 Spike is more stable and binds to the Angiotensin-converting enzyme 2 (ACE2) with higher affinity.

Keywords: B.1.617.2; COVID-19; Computational biology; Mutation; SARS-CoV-2; Spike.

Graphical abstract

Fig. 1

Linear epitopes for native and mutant Spikes identified using ElliPro, tables display epitopes in the same color as structures.

Fig. 2

Discontinuous epitopes for native and mutant Spikes identified using ElliPro, tables display epitopes in the same color as structures.

Fig. 3

Ramachandranot plot of target structures extracted from MD trajectory files.

Fig. 4

Structural dynamic functions obtained from trajectories, A) RMSD, B) RMSF, C) R_g, D) SASA.

Fig. 5

The left panel shows the free energy landscape values for the conformations throughout MD, while the right panel represents principal component analysis for dihedral angels space.

Fig. 6

Secondary structure patterns of mutation positions along with their surrounded residues for native and mutant Spikes.

Fig. 7

PDF plots for mutated positions and their surrounding residues.

Fig. 8

Number of H-bonds for native and mutant Spikes-ACE2 complexes.

Fig. 9

Minimum distance and number of contacts for desired complexes.

Fig. 10

The interaction pattern of ACE2 with native and mutant Spikes. A) 3D structures of Spike-ACE2 (PDB ID: 7DF4), B) Interface residues of Spike-ACE2 complexes, C) Arrangement of mutated positions and surrendered residues.

Fig. 11

Contact and distance map for native and mutant Spikes.

Fig. 12

A) Graphical representation of tunnels and cavities (shown in red) around Pro₆₈₁ and Arg_681, B) Representation of Furin target site in native (left panel) and mutant (right panel) Spikes. As shown in the right panel, the region near the Furin cleavage site is more open in the mutant structure than in the wild-type structure.

Fig. 13

Representation of Furin interaction with native and mutant Spikes in monomeric forms. As can be seen, the active site of Furin interacts in a great manner with its cleavage region in the mutant structure.

Fig. 14

Illustration of oligomerization state of native and mutant Spikes. Reducing the distance between the homomers of the mutant structure can improve Spike oligomerization in the Delta lineage of SARS-CoV-2.

Fig. 15

Schematic representation of different terms of binding free energy throughout MD simulation. A) Apolar solvation energy B) Polar solvation energy C) Electrostatics energy D) VdW energy.

Fig. 16

Decomposition of binding free energy for Spike and ACE2 interface residues; A) ACE2, B) Spike.

Fig. 17

Decomposition of binding free energy (kJ/mol) of mutated positions and residues around them along with related interface residues in the ACE2.

Fig. 18

The complex of Spike-Bamlanivimab (PDB ID: 7KMG); Spike (cyan), Bamlanivimab heavy chain (yellow), Bamlanivimab light chain (purple).

Fig. 19

3D representation of native and mutant Spikes interaction with desired compounds. A) Arbidol (native), B) Arbidol (mutant), C) Isotretinoin (native), D) Isotretinoin (mutant).