Transmembrane Potential of Physiologically Relevant Model Membranes: Effects of Membrane Asymmetry

<div><div>Transmembrane potential difference (𝑉௠) plays important roles in regulating various biological</div><div>processes. At the macro level, 𝑉௠ can be experimentally measured or calculated using the Nernst</div><div>or Goldman-Hodgkin-Katz equation. However, the atomic details responsible for its generation</div><div>and impact on protein and lipid dynamics still need to be further elucidated. In this work, we</div><div>performed a series of all-atom molecular dynamics simulations of symmetric model membranes of</div><div>various lipid compositions and cation contents to evaluate the relationship between membrane</div><div>asymmetry and 𝑉௠. Specifically, we studied the impact of the asymmetric distribution of POPS (1-</div><div>palmitoyl-2-oleoyl-sn-glycero-3-phospho-L-serine), PIP2 (phosphatidylinositol 4,5-bisphosphate),</div><div>𝑁𝑎ା, 𝐾ା and 𝐶𝑎ଶା on 𝑉௠ using atomically detailed molecular dynamics simulations of symmetric</div><div>model membranes. The results suggest that, for an asymmetric POPC-POPC/POPS bilayer in the</div><div>presence of NaCl, enrichment of the monovalent anionic lipid POPS in the inner leaflet polarizes</div><div>the membrane (∆𝑉௠ < 0). Intriguingly, replacing a third of the POPS lipids by the polyvalent</div><div>anionic signaling lipid PIP2 counteracts this effect, resulting in a smaller negative membrane</div><div>potential. We also found that replacing 𝑁𝑎ା ions in the inner region by 𝐾ା depolarizes the</div><div>membrane (∆𝑉௠ > 0), whereas replacing by 𝐶𝑎ଶା polarizes the membrane. These divergent effects</div><div>arise from variations in the strength of cation-lipid interactions and are correlated with changes in</div><div>lipid chain order and head group orientation. </div></div>