Here we explore this issue through atomistic MD simulations (∼5 μs in total), focusing on the β2-adrenergic receptor (β2AR) that is one of the most studied members of the G-protein coupled receptor superfamily. Starting from an inactive-state crystal structure of β2AR, we remove the many modifications in β2AR systematically one at a time, in six consecutive steps. After each step, we equilibrate the system and simulate it quite extensively. The results of this step-by-step approach highlight that the structural modifications used in crystallization can affect ligand and G-protein binding sites, packing at the transmembrane-helix interface region, and the dynamics of connecting loops in β2AR. When the results of the systematic step-by-step approach are compared to an all-at-once technique where all modifications done on β2AR are removed instantaneously at the same time, it turns out that the step-by-step method provides results that are superior in terms of maintaining protein structural stability. The results provide compelling evidence that for membrane proteins whose 3D structure is based on structural engineering, the preparation of protein structure for atomistic MD simulations is a delicate and sensitive process. The results show that most valid results are found when the structural modifications are reverted slowly, one at a time.