Title : Molecular dynamics simulations reveal a novel role for procalcitonin during bacterial induced sepsis
Abstract:
Procalcitonin (PCT) is widely recognized as a key biomarker of sepsis, yet its potential role as an active modulator in a dysregulated immune response remains poorly understood. In this study, we employed all-atom molecular dynamics (MD) simulations via GROMACS to investigate a potential direct interaction between PCT and the Toll-like receptor 4 (TLR4)/myeloid differentiation factor 2 (MD2) complex, a canonical driver of pathogenassociated molecular pattern recognition. Our simulations reveal that PCT establishes stable interactions within the hydrophobic MD2 pocket, inducing conformational rearrangements in the TLR-4 ectodomain consistent with receptor dimerization and downstream activation.
Comparative binding free energy analyses indicated that PCT displays an affinity profile overlapping with that of lipopolysaccharide (LPS), suggesting a mechanistic basis for TLR4-mediated signalling. Furthermore, trajectory-based analysis of hydrogen bonding, solvent accessibility, and dynamic cross-correlation identified structural transitions that are strongly correlated with receptor activation states linked to pro-inflammatory cytokine release. Furthermore, radius of gyration, root mean square deviation/ fluctuation data also indicate PCT is interacting with TLR-4/MD2 complexes. Taken together, these findings support the hypothesis that elevated PCT levels may not only reflect systemic inflammation but also contribute to the amplification of cytokine storm in sepsis through direct TLR4/MD2 stimulation. This work highlights the potential of MD simulation as a predictive tool for uncovering novel host–immune interactions and opens avenues for targeted therapeutic intervention in sepsis.
