۳D modeling of the spike protein in the Omicron variant of the coronavirus and comparison with the Delta and Wuhan strains

The spike protein mediates SARS-CoV-۲ entry into human cells, stimulates neutralizing immune responses in humans, and is the basis of current COVID-۱۹ mRNA vaccines. As the coronavirus spreads, mutations occur in its structure, primarily affecting its spike protein, resulting in multiple variants of this virus. Omicron is the most distinct variant observed in significant numbers during the pandemic, raising concerns that it may be associated with increased transmissibility and reinfection risk and potentially reduce the effectiveness of existing vaccines. This study compares the spike proteins of Delta, Omicron BA.۵, and the Wuhan-Hu-۱ (wild-type) strain, focusing on their binding affinities to ACE۲ and furin, using computational tools to analyze their differences. The spike protein FASTA sequences for Wuhan-Hu-۱, Delta, and Omicron BA.۵ strains were obtained from Uniprot, ViralZone, and NCBI databases. Protein modeling was performed using the Swiss Model server by selecting appropriate templates and building ۳D models. The quality of the models was assessed using the PSVS online tool through Ramachandran plot analysis. Protein domains (S۱, S۲, and RBD) were identified using the Interproscan plugin in the Geneious Prime ۲۰۲۱.۱.۱. The modeled structures were visualized using PyMOL software. Physicochemical parameters were analyzed using ExPASy ProtParam. Sequence alignments were performed using Clustal Omega to identify conserved amino acids and mutations. Intrinsically disordered regions (IDRs) were predicted using the IUPred۳ online tool, which identifies unstructured protein regions by analyzing amino acid interaction energies. The analysis revealed that the Omicron BA.۵ variant has accumulated ۳۶ mutations compared to the Wuhan-Hu-۱ strain and ۳۵ mutations compared to the Delta variant. More than ۴۰% of these mutations are concentrated in the receptor-binding domain (RBD). The Omicron BA.۵ variant demonstrates potentially higher stability due to a higher aliphatic index and an increased number of charged amino acids, potentially resulting in stronger ionic interactions. The furin cleavage site mutation (P۶۸۱H) in Omicron BA.۵ likely enhances protease recognition and viral entry. Moreover, the RBD of Omicron BA.۵ maintains an 'open' conformation, allowing it to be consistently ready for binding with the ACE۲ receptor, which may contribute to its increased transmissibility. This protein variant also displays fewer disordered regions than other variants, indicating a more stable structure. Collectively, these structural changes may explain the enhanced transmissibility and immune evasion capabilities of Omicron BA.۵. This study used bioinformatics tools to compare the spike proteins of the Omicron BA.۵ variant with the Wuhan-Hu-۱ and Delta strains. An analysis of the protein sequences and modeled structures revealed that the spike protein of Omicron BA.۵ has undergone numerous mutations compared to earlier variants. These mutations can influence the protein's physical and chemical properties. Most of these mutations are located in the receptor-binding domain (RBD), which could enhance binding efficiency to the ACE۲ receptor while potentially reducing vaccine effectiveness.

کلیدواژه ها:

Coronavirus ، SARS-CoV-۲ variants ، spike protein ، Omicron BA.۵ ، viral transmissibility ، bioinformatics analysis