Abstract / Summary
Abstract Mutational diversification within the SARS-CoV-2 receptor-binding motif (RBM) continues to reshape the local structural and physicochemical landscape of the receptor-binding domain (RBD), while largely preserving its global fold. Here, we present the first integrated structural and dynamical analysis of the N487 deletion (ΔN487) within the RBM in complex with an engineered ACE2-derived inhibitory peptide. Using 100-ns all-atom molecular dynamics simulations combined with high-accuracy structural modeling, mutation-induced stability profiling, electrostatic potential mapping, and interaction-network analysis, we systematically evaluated how selected RBM mutations—including L452R, N487D, Q493E, and ΔN487—affect RBD conformation and peptide engagement. Among the examined mutations, ΔN487 produced the most pronounced local rearrangements, inducing altered loop orientation, solvent exposure, and surface electrostatics without disrupting the global RBD architecture. The ACE2-derived α-helical peptide maintained conformational stability and persistent α-helicity across native and mutant RBD complexes. Together, these computational findings indicate that RBM deletions can reshape local binding microenvironments without compromising global RBD stability and establish a mechanistic framework for understanding deletion-driven vulnerabilities that may inform future experimental and biophysical validation of peptide-based inhibitors.