Figure 3.

PMF showing the free energy for insertion of (a) niacinamide, (b) N-methylnicotinamide, and (c) isonicotinamide in POPC and POPG model membranes. The PMF is given as a function of the distance from the membrane surface, defined as the average z coordinate of the upper leaflet phosphorus atoms. The lipid headgroups lie roughly in the region –6 Å to 0 (yellow boxes), and the center of the bilayer is at −20 Å (not shown). The location of the molecules in the membrane at the free energy minima are shown in the boxes (red frame for POPC, green frame for POPG; headgroups are shown as red spheres, lipid tails as silver lines, additives as CPK-colored sticks). Unbiased simulations were used to confirm the PMF results and provide more detail on molecular interactions. Additive molecules were initialized at a depth of 5 Å in the membrane, in the region of the free energy minima shown by the PMF curves. We examined all three additives and give example results for the case of niacinamide.