In this study, we propose a structure for the heterodimer between apolipoprotein A-I(Milano) and apolipoprotein A-II (apoA-I(M)-apoA-II) in a synthetic high-density lipoprotein (HDL) containing L-alpha-palmitoyloleoyl phosphatidylcholine. We applied bioinformatics/computational tools and procedures, such as molecular docking, molecular and essential dynamics, starting from published crystal structures for apolipoprotein A-I and apolipoprotein A-II. Structural and energetic analyses onto the simulated system showed that the molecular dynamics produced a stabilized synthetic HDL. The essential dynamic analysis showed a deviation from the starting belt structure. Our structural results were validated by limited proteolysis experiments on HDL from apoA-I(M) carriers in comparison with control HDL. The high sensitivity of apoA-I(M)-apoA-II to proteases was in agreement with the high root mean-square fluctuation values and the reduction in secondary structure content from molecular dynamics data. Circular dichroism on synthetic HDL containing apoA-I(M)-apoA-II was consistent with the alpha-helix content computed on the proposed model.