In silico strategies offer a reliable, fast, and inexpensive, way compared to the clumsy in vitro approaches to boost understanding of the effect of amino acid substitution on the structure and consequently the associated function of proteins. In the present work, we report an atomistic-based, reliable in silico structural and energetic framework of the interactions between the receptor-binding domain of the Interleukin-15 (IL-15) protein and its receptor Interleukin-15α (IL-15α), consequently, providing qualitative and quantitative details of the key molecular determinants in ligand/receptor recognition. Molecular dynamics simulations were used to investigate the dynamic behavior of the specific binding between IL-15 and IL-15α followed by estimation of the free energies via molecular mechanics/generalized Born surface area (MM/GBSA). In particular, residues Y26, E46, E53, and E89 of the IL-15 protein receptor-binding domain are identified as main hot spots, shaping and governing the stability of the assembly. These results can be used for the development of neutralizing antibodies and the effective structure-based design of protein-protein interaction inhibitors against the so-called orphan disease, vitiligo.