A Review of Bioinformatics Studies on the Function of Structural and NonstructuralProteins and the Level of Glycoprotein Inhibiting Heme Metabolismby SARS-CoV-2 Virus

On December 31, 2019, an unknown coronavirus disease was reported from China that cause acute respiratory syndrome which was named COVID-19. This virus was highly contagious and turned into a pandemic in just 3 months. It seems that the high tendency to evolve and the similarity to other viruses of the beta-coronavirus family are the main factors in the susceptibility of this virus to mutation. In all genomes of this virus, the tendency of the virus to spread are varied. However, they are common in human-to-human transmission. The virus can infect one person quickly but not infect others. It can be said that this virus is selective in choosing its host, but the reports have indicated that it has a high rate of 90% in accepting a new host. The angiotensin converting enzyme-2 (ACE-2) receptor is the receptor of SARS-COV-2 to enter human cells. Since the expression level of ACE2 in men living in East Asian countries is higher than in other countries, this population is more susceptible to the virus. In this review study, firs the molecular and cellular characteristics, proliferation, and replication of SARS-COV-2 are investigated. Then, by reviewing bioinformatics studies conducted regarding the analysis of conserved domain and homology and molecular docking, the biological roles of some specific proteins SARS-COV-2 are investigated.

In this study, 60 related articles were reviewed. Then, the information extracted from them were categorized including the types of SARS-COV-2 genomes in different parts of the world and the identified proteins and structural components of these viruses. In this regard, we first reviewed the studies conducted on the genome structure of the SARS-COV-2 and the genetic affinity of SARS-COV-2 to the known coronaviruses. Then, the function of structural and non-structural proteins of coronaviruses was reviewed. Finally, the bioinformatics studies on open reading frames (ORFs) of the virus and the possible origin of SARS-COV-2 were reviewed to know whether it is possible that this virus was created in laboratory or not. This section subdivided into two sections: (a) Bioinformatic study regarding that ORF8 and glycoprotein inhibit Heme metabolism by binding to porphyrin, and (b) bioinformatic study of the genome structure of SARS-COV-2 by examining the mutation in the receptor-binding domain of SARS-COV-2 and the polybasic cleavage site and O-glycan linkage.

Analysis of SARS-COV-2 sequences showed that this virus had a typical genomic structure of beta-coronaviruses, including: Bat SARS-like-ZC45, Bat SARS-like-ZXC21, SARS-CoV and MERS-CoV. According to the phylogenetic tree of coronaviruses (Figure 1), SARS-COV-2 had a high genetic similarity to Bat SARS-like-ZC45 and Bat SARS-like-ZXC21, while SARS-CoV had the lowest similarity to them.In this study, it was found that ORF8 and surface glycoprotein can bind to porphyrin, and ORF1ab, ORF10 and ORF3a can attack the heme part of hemoglobin to dissociate iron and form porphyrin. This attack causes a decrease in the hemoglobin to carry oxygen and carbon dioxide. Lung cells become inflamed due to the inability to exchange carbon dioxide and oxygen, which leads to large ground-glass opacities in CT scan images. The three-dimensional image of the structures of three viral proteins (surface glycoprotein, envelope protein, and nucleocapsid phosphoprotein) was downloaded from the PDB database. The structural model indicated the inability of the surface glycoprotein to bind to the porphyrin in Heme, while the envelope protein could bind to porphyrin. For the phosphoprotein nucleocapsid, the results indicated the ability of this protein to bind to porphyrin with the highest possible binding energy (5206.53 kcal/mol). Figure 2 shows the docking results, a two-dimensional view of the binding sections of the envelope protein and nucleocapsid phosphoprotein with human porphyrin. Figure 3 illustrated the two-dimensional view of the binding sections of viral non-structural protein ORF8 with human porphyrin.

Based on the structural studies performed on SARS-COV-2, it seems that this virus can bind to the human cell receptor ACE-2. The S protein of SARS-COV-2 has a functional polybasic cleavage site called “Furin” at the S1/S2 boundary, which is formed by 12 nucleotides, resulting in three O-glycan binding sites around this polybasic cleavage site. Since the COVID-19 pandemic is a global problem, predictive methods to search for the protected domains of the virus are very important. Achieving the structure of protein molecules including ORF8 and nucleocapsid phosphoproteins (surface proteins) using bioinformatics study and analyzing the possibility and the method of their binding to human porphyrin in the heme part of hemoglobin is needed. According to the review of the bioinformatics studies, chloroquine can prevent ORF1ab, ORF10 and ORF3a from attacking hemoglobin to form porphyrin, and avoid the binding of ORF8 and surface glycoproteins to porphyrin to a certain extent, which effectively relieves acute respiratory symptoms. The results of bioinformatics studies are of high value in preventing the spread of COVID-19, developing drugs and vaccines, and clinical practice.