The binding of the C2AB domain of the calcium sensor synaptotagmin-1 (Syt1) to lipid bilayers is a critical step in triggering neurotransmitter release at nerve terminals. However, effective regulation of this binding remains a significant challenge. In this study, we used all-atom molecular dynamics (MD) simulations to explore the underlying mechanisms of the $\mathrm{C}2\mathrm{AB}/\mathrm{C}{\mathrm{a}}^{2+}\_\mathrm{C}2\mathrm{AB}$ interaction with lipid bilayers and examined how external terahertz (THz) waves influence this binding. We first identified the key residues and interactions involved in $\mathrm{C}2\mathrm{AB}/\mathrm{C}{\mathrm{a}}^{2+}\_\mathrm{C}2\mathrm{AB}$ binding to phospholipids in the absence of THz waves. Then, we analyzed the effects of 42.55 THz waves on the binding dynamics. Importantly, the predominant vibration mode at 42.55 THz waves induces rotational movements of negatively charged phospholipid heads by affecting the vibrations of $-\mathrm{CO}{\mathrm{O}}^{-}$ and $-\mathrm{CH}$ bonds. This shift alters charge distributions within the lipid bilayers, increasing the distance between certain residues and phospholipids, and consequently reducing the binding energy. Overall, our findings suggest that THz radiation can act as a novel modulator of neurotransmitter release by disrupting the Syt1–phospholipid interaction, offering potential insights into the regulation of synaptic activity.

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• Protein-membrane interactions
• Molecular dynamics