The interplay between an enzyme and its natural substrate is a complex biological phenomenon whose fine details, most of the times, elude us. Although experimental techniques are invaluable tools to highlighting some aspects of the process, they cannot provide a detailed description of the mutual structural rearrangements occurring during the recognition and binding phases. Hence, it is tempting to use computational tools to unravel the principles of such events. Here, we use state of the art computational procedures to describe at atomic level the docking process of cortisone to its naturally catalysing enzyme, type 1 11β-hydroxysteroid dehydrogenase and to the Y177A mutant. The study highlights significant mechanistic details of the enzyme upon substrate binding that allow a better understanding of some recently published experimental data. We show that it is possible to use computational models to capture the multifaceted relationship between bio-molecules and to complement experiments in unveiling the fine nature of complex molecular mechanisms.