Structural and Functional Impacts of SARS-CoV-2 Spike Protein Mutations: Insights From Predictive Modeling and Analytics.

Background: The COVID-19 pandemic requires a deep understanding of SARS-CoV-2, particularly how mutations in the spike receptor-binding domain (RBD) chain E affect its structure and function. Current methods lack comprehensive analysis of these mutations at different structural levels. Objective: This study aims to analyze the impact of specific COVID-19-associated point mutations (N501Y, L452R, N440K, K417N, and E484A) on the SARS-CoV-2 spike RBD structure and function using predictive modeling, including a graph-theoretic model, protein modeling techniques, and molecular dynamics simulations. Methods: The study used a multitiered graph-theoretic framework to represent protein structure across 3 interconnected levels. This model incorporated 19 top-level vertices, connected to intermediate graphs based on 6-angstrom proximity within the protein's 3D structure. Graph-theoretic molecular descriptors or invariants were applied to weigh vertices and edges at all levels. The study also used Iterative Threading Assembly Refinement (I-TASSER) to model mutated sequences and molecular dynamics simulation tools to evaluate changes in protein folding and stability compared to the wildtype. Results: A total of 3 distinct predictive modeling and analytical approaches successfully identified structural and functional changes in the SARS-CoV-2 spike RBD (chain E) resulting from point mutations. The novel graph-theoretic model detected notable structural changes, with N501Y and L452R showing the most pronounced effects on conformation and stability compared to the wildtype. K147N and E484A mutations demonstrated less significant impacts compared to the severe mutations, N501Y and L452R. Ab initio modeling and molecular simulation dynamics findings corroborated the results from graph-theoretic analysis. The multilevel analytical approach provided a comprehensive visualization of mutation effects, deepening our understanding of their functional consequences. Conclusions: This study advanced our understanding of SARS-CoV-2 spike RBD mutations and their implications. The multifaceted approach characterized the effects of various mutations, identifying N501Y and L452R as having the most substantial impact on RBD conformation and stability. The findings have important implications for vaccine development, therapeutic design, and variant monitoring. Our research underscores the power of combining multiple predictive analytical approaches in virology, contributing valuable knowledge to ongoing efforts against the COVID-19 pandemic and providing a framework for future studies on viral mutations and their impacts on protein structure and function.