In the second stage of the parameterization, we required that the resulting parameters reproduced a wide range of experimentally derived top-down properties, for example, geometrical features like bilayer area per lipid and thickness, and thermodynamical properties like phase change behavior. This second stage is a highly non-linear and multidimensional optimization problem that is inherently difficult to solve, especially with a relatively small set of fitting parameters, i.e. general bonded parameters and bead type choices to be used in all lipid-related molecules. Furthermore, due to the simulation turnover time of evaluating top-down properties like phase change behavior, which requires substantial MD sampling, fully automating the second stage was not feasible, and we instead relied on human-in-the-loop decisions and compromises between bottom-up and top-down properties through rational design.