Chodnicki, P. | bioRxiv Science

bioRxiv2025

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

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.

biophysics↗

bioRxiv2021

Determinants of directionality and efficiency of the ATP synthase Fo motor at atomic resolution

Fo subcomplex of ATP synthase is an membraneembedded rotary motor that converts proton motive force into mechanical energy. Despite a rapid increase in the number of high-resolution structures, the mechanism of tight coupling between proton transport and motion of the rotary c-ring remains elusive. Here, using extensive all-atom free energy simulations, we show how the motors directionality naturally arises from the interplay between intra-protein interactions and energetics of protonation of the c-ring. Notably, our calculations reveal that the strictly conserved arginine in the a-subunit (R176) serves as a jack-of-all-trades: it dictates the direction of rotation, controls the protonation state of the proton-release site and separates the two proton-access half-channels. Therefore, arginine is necessary to avoid slippage between the proton flux and the mechanical output and guarantees highly efficient energy conversion. We also provide mechanistic explanations for the reported defective mutations of R176, reconciling the structural information on the Fo motor with previous functional and single-molecule data.

biophysics↗