Principal Component Analysis to evaluate the stability impact of protein mutations: the case of SARS-CoV-2 K417T mutation

The severe acute respiratory syndrome CoV-2 (SARSCoV-2), which was initially identified in the Wuhan Province, China spread worldwide rapidly. The intense escalation forced the WHO to declare a pandemic with 6.5 million deaths worldwide. The SARS-CoV-2 virus has a wide host range, as it uses the angiotensin-converting enzyme 2 (ACE2) as a target receptor in humans. A 211 amino acid region at the C-terminal domain of the S1 subunit of the coronavirus as the receptor/binding domain was identified through structural and biochemical analyses. This plays a crucial role in virus entry and is the main target of the host immune responses. The RBD mediates contact with the ACE2 receptor and RBD region in SARS-CoV-2 varies from the one in other SARS-CoV viruses in the five residues critical for ACE2 binding. As a result of these changes, the interaction of SARS-CoV-2 with its receptor stabilizes the two virus-binding hotspots on the surface of hACE2. Moreover, four-residue motif in the RBM of SARS-CoV2 leads to a more compact conformation of its hACE2binding bridge. While the SARS-CoV-2 S protein lost some of its key mutations which are associated with higher infectivity (Stojanov, 2021), many SARS-CoV-2 variants possess stronger virulence and infectivity and can produce immune escape. Several RBD residues mutated independently in multiple lineages. The RBD residues 331–524 of the Spike protein have been a prime focus in many studies. These mutations include N501Y in the Alpha, Beta, Gamma, and Omicron variants; K417 mutated to N in the Beta, Delta, and Omicron variants and to T in the Gamma variant, and E484 mutated to K in the Beta and Gamma variants and to A in the Omicron variant. The purpose of this study was to examine and analyse the impact of K417T mutation upon SARS-CoV-2 Sprotein/hACE2 complex stability through the process of PCA analysis.