Abstract
The structural spike (S) protein from the SARS-CoV-2 β-coronavirus is shown to make different pre- and post-fusion conformations within its homotrimer unit. To support the ongoing novel vaccine design and development strategies, we report the structure-based design approach to develop self-derived S peptides. A dataset of crucial regions from the S protein were transformed into linear motifs that could act as the blockers or stabilizers for the S protein homotrimer unit. Among these distinct S peptides, the pep02 (537-QQFGRDIAD-545) and pep07 (821-RDLICAQKFNGLTVLPPLLTDE-842) were found making stable folded binding with the S protein (550-750 and 950-1050 regions). Upon inserting SARS-CoV-2 S variants in the peptide destabilized the complexed S protein structure, resulting an allosteric effect in different functional regions of the protein. Particularly, the molecular dynamics revealed that A544D mutation in the pep02 peptide induced instability for the complexed S protein, whereas the N943K variant from pep09 exhibited an opposite behavior. An increased protein-peptide binding affinity and the stable structural folding were observed in mutated systems, compared to that of the wild type systems. The presence of mutation has induced an “up” active conformation of the spike (RBD) domain, responsible for interacting the host cell receptor. Among the lower affinity peptide datasets (e.g., pep01), the S1 and S2 subunit in the protein formed an “open” conformation, whereas with higher affinity peptides (e.g., pep07) these domains gained a “closed” conformation. These findings propose that our designed self-derived S peptides could replace a single S protein monomer, blocking the homotrimer formation or inducing stability.
Keywords: COVID; Linear motif; Molecular dynamics; RBD; SARS-CoV-2; Self-derived peptides; Spike; Structural folding; Vaccine.
【저자키워드】 SARS-CoV-2, spike, molecular dynamics, vaccine., COVID, RBD, Linear motif, Self-derived peptides, Structural folding, 【초록키워드】 Mutation, S protein, Vaccine design, variant, peptide, molecular dynamics, binding affinity, Protein, Region, stability, peptides, protein structure, dataset, structure-based design, molecular, wild type, S2 subunit, binding, host cell, Support, subunit, domain, conformation, host cell receptor, SARS-CoV-2 S, blocker, blockers, monomer, higher affinity, motif, opposite, β-coronavirus, instability, regions, approach, S1 and S2 subunit, shown, responsible, resulting, S1 and S2, develop, linear, exhibited, functional, mutated, the S protein, destabilized, homotrimer, the SARS-CoV-2, 【제목키워드】 spike glycoprotein, stability, disrupting, homotrimer, the SARS-CoV-2,