Transmembrane potential difference (𝑉௠) plays important roles in regulating various biological

processes. At the macro level, 𝑉௠ can be experimentally measured or calculated using the Nernst

or Goldman-Hodgkin-Katz equation. However, the atomic details responsible for its generation

and impact on protein and lipid dynamics still need to be further elucidated. In this work, we

performed a series of all-atom molecular dynamics simulations of symmetric model membranes of

various lipid compositions and cation contents to evaluate the relationship between membrane

asymmetry and 𝑉௠. Specifically, we studied the impact of the asymmetric distribution of POPS (1-

palmitoyl-2-oleoyl-sn-glycero-3-phospho-L-serine), PIP2 (phosphatidylinositol 4,5-bisphosphate),

𝑁𝑎ା, 𝐾ା and 𝐶𝑎ଶା on 𝑉௠ using atomically detailed molecular dynamics simulations of symmetric

model membranes. The results suggest that, for an asymmetric POPC-POPC/POPS bilayer in the

presence of NaCl, enrichment of the monovalent anionic lipid POPS in the inner leaflet polarizes

the membrane (∆𝑉௠ < 0). Intriguingly, replacing a third of the POPS lipids by the polyvalent

anionic signaling lipid PIP2 counteracts this effect, resulting in a smaller negative membrane

potential. We also found that replacing 𝑁𝑎ା ions in the inner region by 𝐾ା depolarizes the

membrane (∆𝑉௠ > 0), whereas replacing by 𝐶𝑎ଶା polarizes the membrane. These divergent effects

arise from variations in the strength of cation-lipid interactions and are correlated with changes in

lipid chain order and head group orientation.

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