Effects of SARS-CoV-2 Mutations on Protein Structures and Intraviral Protein-Protein Interactions

Abstract

Since 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing coronavirus disease 2019 (COVID-19) has infected ten millions of people across the globe, and massive mutations in virus genome have occurred during the rapid spread of this novel coronavirus. Variance in protein sequence might lead to change in protein structure and interaction, then further affect the viral physiological characteristics, which could bring tremendous influence on the pandemic. In this study, we investigated 18 non-synonymous mutations in SARS-CoV-2 genome which incidence rates were all ≥1% as of July 15th, 2020, then modeled the mutated protein structures and compared them with the reference ones. The results showed that four types of mutations could cause dramatic changes in protein structures (RMSD ≥5.0 Å), which were Q57H and G251V in open reading frames 3a (ORF3a), S194L and R203K/G204R in nucleocapsid (N). Next, we found that these mutations could affect the binding affinity of intraviral protein interactions. In addition, the hot spots within these docking complexes were altered, among which the mutation Q57H was involved in both Orf3a-Orf8 and Orf3a-S protein interactions. Besides, these mutations were widely distributed all over the world, and their occurrences fluctuated as time went on. Notably, the incidences of R203K/G204R in N and Q57H in Orf3a were both over 50% in some countries. Overall, our findings suggest that SARS-CoV-2 mutations can change viral protein structure, binding affinity and hot spots of the interface, thereby may have impacts on SARS-CoV-2 transmission, diagnosis and treatment of COVID-19.

Molecular characterization of SARS-CoV-2 from Bangladesh: Implications in genetic diversity, possible origin of the virus, and functional significance of the mutations

“…Though functionally tolerated this change was predicted to decrease the protein stability. This finding is similar with other studies that reported R203K and G204K destabilizes N protein structure but may enhance interaction with SARS-CoV-2 Envelop protein that may promote viral release (53,54).…”

“…There two other functionally significant mutations which are Q57H in ORF3a and S194L in N protein. Our analysis suggested the Q57H decreases protein stability with altered protein function may result in loss of a CD4+ T Cell epitope similar to other studies (53,56). The S194L was predicted to have neutral effect in our study with a reduced DDG value and may attenuate viral assembly as reported in an earlier study (53).…”

Molecular dynamics simulation study reveals effects of key mutations on spike protein structure in SARS-CoV-2

“…Mutation is one of the main mechanisms by which viruses are constantly changing due to genetic selection. Although most point mutations are neutral and do not alter the protein the gene codes for, a few favorable mutations can give an evolutionary advantage to viruses (Wu et al, 2020). The D614G substitution in the gene encoding the spike protein emerged in late January or early February 2020, and emerged in Europe around 2020 February 22 (Korber et al, 2020).…”

“…A222V has recently been reported as a rapidly increasing genotype (Bartolini et al, 2020; Ward et al, 2021). Q57H of ORF3a has been reported that it shows an opposing association with decreased deaths and increased cases per million (Oulas et al, 2021), It also causes significant structural changes that affect the interaction between ORF3a and other proteins (Wu et al, 2020). From the level of molecular simulation, our study explored the change of protein traits when D614G and A222V were coupled for S protein, and the influence of Q57H on protein traits for ORF3a protein.…”

SARS‐CoV‐2, the pandemic coronavirus: Molecular and structural insights

“…Four such mutations (Q57H and G251V in ORF3a, R203K/G204R in N proteins) have been reported. Q57H increases the affinity of ORF3a for S and N proteins resulting in an impact on virus budding and release [149]. On the contrary, some mutations (like P323L in NSP12 and D614G in S protein) do not affect the protein biology of the virus but play a role in RNA structures [150].…”