Lipid Dynamics and Organization Around Voltage-Gated Sodium Channels: A Coarse-Grained Perspective

Abstract

Lipid-ion channel interactions play a critical role in channel function and membrane structural organization. Despite this importance, the mechanisms behind the rearrangement of lipids around ion channels are still unclear. To investigate this, we conducted coarse grained (CG) molecular dynamics simulations of voltage gated sodium ion channels (NavAB) embedded in a ternary lipid bilayer composed of 1,2-dilinoleoyl-sn- glycero-3-phosphocholine (DIPC), 1,2-dipalmitoyl-sn-glycero- 3-phosphocholine (DPPC), and cholesterol (CHOL) at varying CHOL concentrations (6.62%, 17.62% and 30.00%). By analyzing lipid organization and membrane structure, we examined how membrane composition and channel state (activated and resting) influence lipid redistribution near the channel interface. Our key finding is a pronounced preference for DIPC for the channel vicinity, observed consistently for all CHOL concentrations and channel states. Our simulations reveal that hydrophobic mismatch dictates lipid sorting near NavABs. The hydrphobic thickness of the channel favors flexible DIPC lipids, which are packed efficiently around it, while excluding thicker DPPC lipids. This exclusion drives DPPC and cholesterol to form ordered domains farther from the channel interface. Mixing entropy analysis supports local lipid de-mixing near the channel, aligning with the emergence of phase-separated domains. Notably, the hydrophobic thickness of NavAB remained stable and in close agreement with the experimental values, indicating that lipid-specific properties drive reorganization near the channel. Overall, our findings demonstrate that hydrophobic mismatch is a key driver of lipid reorganization and domain formation around ion channels, regardless of CHOL concentration or channel conformational state.