Synergistic antibody neutralization of SEB is driven by allosteric transfer entropy

Allosteric effect correlates amino acid residues with entropy transfer with and within proteins in a protein complex. The solvation effect could play roles in shaping the allosteric effects. Here we investigate multiple levels of global allosteric correlations within and among proteins in a quaternary antibody-toxin complex, including perturbations of water molecules within first and second solvation shells during all atom MD simulations. Staphylococcal enterotoxin B (SEB) is a potent exotoxin. While monoclonal antibodies 6D3 and 14G8 bind SEB, neither confers significant protection individually, as their epitopes are distal to the TCR/MHC-II interface. Intriguingly, their combination results in potent synergistic neutralization. Our analysis reveals that the simultaneous binding of 14G8 and 6D3 exerts long-range allosteric effects, altering residue fluctuations within the SEB-TCR-binding region. Transfer entropy analysis further demonstrated that the antibody combination establishes an allosteric network that directly modulates the TCR-binding interface. Finally, conformational and solvent entropy analyses suggest that synergistic antibody-mediated inhibition of SEB-TCR binding is caused by increasing SEB's entropy and saturated entropic dissipation into solvent. This study highlights the importance to incorporate environment factors into the allosteric mechanism and provides a systematic comparison of antibody-induced allostery in SEB and, through transfer entropy modeling, establishes a dominant role for specific antibodies in regulating antigen dynamics, offering novel insights into synergistic neutralization mechanisms.