Can SARS-CoV-2 Accumulate Mutations in the S-Protein to Increase Pathogenicity?

Abstract

SARS-CoV-2 has developed a substantial number of mutations, especially in the S-protein. With the advancement of the pandemic, accumulations of further mutations at the S-protein receptor-binding domain could enhance the infectivity and pathogenicity of the virus. Prediction and evaluation of such mutations are essential for understanding the potential development of more pathogenic strains and for COVID-19 management.

Figure 1

Structures and interactions in RBD–ACE2 complexes. (A) Ribbon structure of SARS-CoV-2 RBD in complex with human ACE2 (Protein Data Bank (PDB): 6LZG), showing the residues of S-protein RBD interacting with ACE2 receptor. The residues interacting between RBD–ACE2 are represented in orange sticks. Intermolecular interactions in (B) an affinity-increasing and (C) an affinity-decreasing RBD–ACE2 complex. In all the panels, the RBD and ACE2 are shown in cyan and green color, respectively. The interacting residues and binding sites in panel B are shown in purple sticks, and in panel C are shown in red sticks.

Figure 2

Schematic representation of the viewpoint. S-protein RBD can undergo mutations under positive selection pressure to generate variations to increase affinity with ACE2, creating strains with increased infectivity. Here, the hot-spot residues responsible for improved interactions can be identified. The RBD can also undergo mutations under negative selection pressure to generate variations to decrease affinity with ACE2, producing less pathogenic strains. Here, the cold-spot residues responsible for decreased interactions can be identified. The hot- and cold-spot residues can be used to design therapeutic strategies for COVID-19.