Molecular Mechanism of Evolution and Human Infection with SARS-CoV-2

Abstract

The outbreak of a novel coronavirus, which was later formally named the severe acute respiratory coronavirus 2 (SARS-CoV-2), has caused a worldwide public health crisis. Previous studies showed that SARS-CoV-2 is highly homologous to SARS-CoV and infects humans through the binding of the spike protein to ACE2. Here, we have systematically studied the molecular mechanisms of human infection with SARS-CoV-2 and SARS-CoV by protein-protein docking and MD simulations. It was found that SARS-CoV-2 binds ACE2 with a higher affinity than SARS-CoV, which may partly explain that SARS-CoV-2 is much more infectious than SARS-CoV. In addition, the spike protein of SARS-CoV-2 has a significantly lower free energy than that of SARS-CoV, suggesting that SARS-CoV-2 is more stable and may survive a higher temperature than SARS-CoV. This provides insights into the evolution of SARS-CoV-2 because SARS-like coronaviruses have originated in bats. Our computation also suggested that the RBD-ACE2 binding for SARS-CoV-2 is much more temperature-sensitive than that for SARS-CoV. Thus, it is expected that SARS-CoV-2 would decrease its infection ability much faster than SARS-CoV when the temperature rises. These findings would be beneficial for the disease prevention and drug/vaccine development of SARS-CoV-2.

Keywords: MD simulations; SARS-CoV; SARS-CoV-2; coronaviruses; human infection; molecular mechanism; protein docking.

Figure 1

Protein-protein docking with SARS-CoV-2 receptor binding domain (RBD) and human angiotensin-converting enzyme II (ACE2). (A) Structural comparison between the predicted SARS-CoV-2 RBD-ACE2 complex and the experimental SARS-CoV RBD-ACE2 structure (PDB code: 3SCI). SARS-CoV-2 RBD is colored magenta and its interacting ACE2 is colored blue. SARS-CoV RBD is colored green and its interacting ACE2 is colored red, respectively. (B) The binding site residues on the RBD that are within 5.0 Å form the ACE2, where the hydrophobic residues on the SARS-CoV-2 RBD are highlighted in red. (C) Part of the sequence alignment between the spike proteins of SARS-CoV-2 and SARS-CoV, where the RBD residues are highlighted in yellow and the residues at the binding site are highlighted in magenta, respectively.

Figure 2

Structural comparison between the predicted and experimental SARS-CoV-2 RBD-ACE2 complexes. (A) Alignment of the predicted and experimental SARS-CoV-2 RBD-ACE2 complexes. (B) Alignment of the predicted and experimental RBD structures. The RBD and ACE2 of the predicted complex are colored pink and blue. The RBD and ACE2 of the experimental complex (PDB code: 6M17) are colored green and red.

Figure 3

The conformational flexibility of the RBD protein. (A) The 50 representative trajectories of the SARS-CoV-2 RBD protein over a 10 ns MD simulation, where the highly flexible region (residues 470–490) is indicated by a circle. (B) The 50 representative trajectories of the SARS-CoV RBD protein over a 10 ns MD simulation. (C) The RMSFs for the RBD proteins of SARS-CoV-2 and SARS-CoV, where the residue numbering is taken from the SARS-CoV-2 RBD and the data of SARS-CoV are then aligned to those of SARS-CoV-2 according to the sequence alignment.