Discussion
The COVID-19 epidemic is spreading as an unsolvable problem worldwide.
Despite the efforts of researchers, many details on SARS-CoV-2 biology
remain unknown. Our study focused on the Nsp1 structure and stability by
using different computational tools. We found that SARS-CoV-2 Nsp1 has a
reduced compactness in comparison with SARS-CoV-1 Nsp1, with an increase
in structural movements, suggesting this protein can more easily
approach the active site of the ribosome compared to SARS-CoV-1 Nsp1. In
addition, we found that the C-terminal of the SARS-CoV-2 Nsp1, in
particular residues 164 to 170, are more flexible than other regions of
SARS-CoV-2 Nsp1 and SARS-CoV-1 Nsp1, confirming the role of this region
in the interaction with the 40S subunit.
Interestingly, a previous study suggested that when SARS-CoV-2 5′-UTR
bind to Nsp1 N-terminal, the covalently linked Nsp1 C-terminal is not
able to bind the 40S subunit [38]. The authors
suggest that this may be due to a steric factor in which Nsp1 C-terminal
is unable to approach the 40S subunit to form the Nsp1-ribosome complex.
We found that mutation R24C had the highest frequency among all protein
substitution mutations identified by us. Therefore, the occurrence of
this mutation in the Nsp1 N-terminal may change the affinity of Nsp1
binding to the 5′-UTR of SARS-CoV-2, perhaps making it more effective in
using the host ribosome for translation of viral proteins.
The Nps1 C-terminal was identified as being intrinsically disordered. In
addition, E155, F157, D156, Q158, V169, T170, L173, F172, M174, and N178
emerged from the RIN analysis of betweenness and stress as 10 key
residues governing the stability and affinity of the Nsp1 for
interaction with ribosome. We also found that 11 mutations at HTH motif,
which affect the Nsp1 structure, stability and binding affinity.
Structural studies revealed that IDRs influence viral genome (RNA)
adaptive capacity, host-virus interactions, virus-host range,
cross-species transmission, and host tropism[39–43]. In antigen selection, IDRs may induce an
undesirable immune response, such as weak or even completely non-immune
responses [44]. Thus, these results indicated that
IDRs may affect the interaction between the Nsp1 and the ribosome. If
Nsp1 is used as an antigen, it may lead to an inappropriate immune
response due to the presence of CT IDRs.