As a necessary check for the validation of the data sets produced by our optimization setup, we computed the lateral pressure profiles ∆P (z) for the optimized lipid bilayers, defined as: As previously shown using BO-optimized parameters for DPPC in HhPF simulations, the main features of ∆P (z) could be reproduced without directly introducing any related information in the learning function. Using DPPC for direct comparison, the lateral pressure profile is in excellent quantitative agreement with the one produced by all-atom data, improving the profiles obtained with the BO-optimized parameters. In particular, the lateral pressure profiles feature a weakly negative balance in the membrane core and a large positive fluctuation at the height of the polar head. Notably, in the same region, the stretching, and bending terms provide This is consistent with the sharper distribution of the polar heads reported in the density profiles (Fig. ), corresponding to a more regular alignment of the bonded moieties along the normal axis of the membrane. Compared to the all-atom model, the pressure profile underestimates the negative fluctuations in the outer part of the bilayer, similar to the BO model. As already discussed there, this is attributed to the poor representation of the solvation structure, which is an intrinsic weakness of the CG mapping itself. However, compared to the BO model, in this case, we managed to almost perfectly match the inner all-atom peaks, both in terms of intensity and position along the normal to the membrane. The qualitatively correct behavior of the lateral pressure profile across the whole membrane validates the soundness of the physics represented by the models and, thus, their reliability for future use in other application studies. Fig. in the Supporting Information reports the complete table of lateral pressure profiles for all the other systems.