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Abstract
Transmembrane potential difference (πΰ― ) plays important roles in regulating various biological
processes. At the macro level, πΰ― 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 πΰ― . 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),
ππΰ¬Ύ, πΎΰ¬Ύ and πΆπΰ¬Άΰ¬Ύ on πΰ― 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 (βπΰ― < 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 ππΰ¬Ύ ions in the inner region by πΎΰ¬Ύ depolarizes the
membrane (βπΰ― > 0), whereas replacing by πΆπΰ¬Άΰ¬Ύ 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.
