Influence of Membrane Composition on the Passive Membrane Penetration of Industrially Relevant NSO-Heterocycles.

This study investigates how phospholipid headgroups influence passive membrane penetration and structural impact of four nitrogen-, sulfur-, and oxygen-containing heterocycles (NSO-HETs)-N-methyl-2-pyrrolidone (PIR), 1,4-dioxane (DIOX), oxane (OXA), and phenol (PHE). Using all-atom molecular dynamics simulations combined with Accelerated Weight Histogram free energy calculations, the passive transport of NSO-HETs across DPPC, DPPE, DPPA, and DPPG bilayers was characterized. DPPG showed the highest membrane affinity, increasing permeability (logP) by 27-64% compared to DPPE, associated with the lowest permeability and tightest lipid packing. Free energy barriers are also decreased in DPPG relative to DPPE; PIR's central barrier dropped from 19.2 kJ/mol (DPPE) to 16.6 kJ/mol (DPPG), while DIOX's barrier decreased from 7.2 to 5.2 kJ/mol. OXA exhibited the lowest central barriers (1.2-2.2 kJ/mol) and uniquely accumulated at higher concentrations in the bilayer center than in bulk water, with free energy ranging from -3.4 to -5.9 kJ/mol. PHE and OXA caused significant bilayer thinning (up to 11%) and reduced lipid tail order, especially in DPPE and DPPA. Concentration effects were most pronounced in DPPE, where high solute loading disrupted lipid order and altered free energy profiles. These results highlight the crucial role of headgroup identity in modulating NSO-HET membrane permeability and structural changes.