Interfacial Water Structure at Zwitterionic Membrane/Water Interface: The Importance of Interactions between Water and Lipid Carbonyl Groups

[Image: see text] In this work, atomistic molecular dynamics (MD) simulations of palmitoyl-oleoyl-phosphatidylcholine (POPC) bilayer were carried out to investigate the effect of water models on membrane dipole potential, which is primarily associated with the preferential orientation of molecular dipoles at the membrane–water interface. We discovered that the overestimation of the dipole potential by the TIPS3P water model can be effectively reduced by the TIP4P water model. On the one hand, the TIP4P water model decreases the negative contribution of lipid to the dipole potential through influencing the orientation of lipid headgroups. On the other hand, the TIP4P water model reduces the positive contribution of water to the dipole potential by increasing the preference of H-down orientation (the water dipole orients toward the bilayer center). Interestingly, the TIP4P water model affects the orientation of interfacial water molecules more obviously than that of lipid headgroups, leading to the decrease in the dipole potential. Furthermore, the MD results revealed that the water close to the positively charged choline (namely, N-associated water) prefers the H-down orientation while the water around the negatively charged phosphate (namely, P-associated water) favors the H-up orientation, in support of recent experimental and MD studies. However, interfacial water molecules are more strongly influenced by the phosphate groups than by the choline groups, resulting in the net H-up orientation (the water dipole orients toward the bilayer center) in the region of lipid headgroups. In addition, it is intriguing that the preference of H-up orientation decreases when water molecules penetrate more deeply into the lipid bilayer. This is attributed to the counteracting effect of lipid carbonyl groups, and the effect varies with the lipid chains (oleoyl and palmitoyl chains), suggesting the important role of lipid carbonyl groups.