Dystrophin-β-dystroglycan interaction has gained a special attention during current years due to its association with the pathogenesis of muscular dystrophies. Dystrophin is an important component of dystrophin associated protein complex that functions in the normal physiology and cell signaling in addition to membrane stabilization and provides integrity to skeletal muscle fibers. WW, EF-hand and ZZ domains of dystrophin are known to bind with extreme C-terminal region of beta-dystroglycan (β-DG) containing PPxY motif and this interaction is experimentally proven to be coordinated and regulated by two tyrosine (Tyr and Tyr) residues in the C-terminus of beta-dystroglycan. These tyrosine residues are phosphorylated in adhesion dependent manner that disrupts dystrophin-β-DG interaction. The failure of dystrophin to interact with β-DG causes muscular dystrophies. In this study, we have performed molecular docking analysis of dystrophin with phosphorylated and mutated variants of β-DG to pinpoint the actual nature of this interaction at molecular level. We have discovered significant structural and conformational changes in β-DG molecule caused by mutations and tyrosine phosphorylation that alter the nature and site of its interaction with dystrophin. Our results not only support the previous findings but also bring to attention previously unreported discoveries about the nature of this interaction and behavior of different β-DG variants with dystrophin WW, EF-hand and ZZ domains.