Computational screening and molecular modeling of probiotic-derived peptides targeting the conserved HR1 domain of...

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of the global COVID-19 pandemic, relies on its spike glycoprotein to mediate host cell entry via binding to human angiotensin-converting enzyme 2 (hACE2). The S2 subunit of the spike protein contains heptad repeat regions (HR1 and HR2) that form a six-helix bundle fusion core, a critical step for viral-host membrane fusion. This study aimed to computationally screen a library of 318 probiotic-derived bacteriocins to identify potential inhibitors targeting the conserved HR1 domain. Evaluation included historical variants (Alpha, Beta, Gamma, Kappa, Epsilon, Omicron) and currently circulating strains (BA.2.86, EG.5.1, HV.1, JN.1). Methodologies included: sequence conservation analysis via Clustal Omega, protein-peptide docking using HADDOCK 2.4 with Ambiguous Interaction Restraints derived from the HR1-HR2 complex (PDB: 6LXT), safety profiling with AlgPred, ToxinPred, HemoPred, TargetAntiAngio, and IL-4Pred, and molecular dynamics simulations (GROMACS 2020) assessing RMSD, RMSF, and hydrogen bonds. Results identified plantaricin K (2KEG) as a high-affinity binder to HR1 across all tested variants, with favorable in silico safety profiles (non-toxic, non-allergenic, non-hemolytic). Simulation data confirmed stable binding of 2KEG to HR1, supporting its role as a fusion inhibitor. These findings suggest the potential of probiotic-derived bacteriocins, particularly 2KEG, as broad-spectrum antiviral candidates against SARS-CoV-2. Further experimental studies are required to validate these computational predictions.