Current genetic therapies for Duchenne muscular dystrophy (DMD) focus on the use of mini-dystrophin constructs based on Becker muscular dystrophy (BMD) patients. Previous studies have shown that these mini-dystrophin constructs function because they contain in-frame deletions that preserve the helical structure of the spectrin domains. However, some dystrophy patients with supposedly in-frame deletions may still have the severe form of the disease. Therefore, preservation of the helical structure is not an adequate predictor of the functionality of the mini-dystrophin construct. Three Becker based dystrophin nano-constructs were examined using homology studies and molecular dynamics. These studies focused on the altered linker regions introduced by their respective exon deletion(s). Results show that these linker regions contain one or more spectrin-like domains that are stable in solution. Furthermore the nature of the helical packing in the triple coiled-coil is the main commonality between functional mini-constructs. In-vitro and in-vivo studies have shown that spectrin domains can unfold and refold inside the cell, and the effect of deletions on this function and its biological implications are discussed. Structural principles gleaned from these studies are also used to design a novel dystrophin construct with increased therapeutic function.