The transient receptor potential (TRP) channel TRPV4 is a calcium-permeable cation channel protein which plays a mechanosensory and osmosensory role in several musculoskeletal tissues. Previous studies have shown that some specific mutations in the ankyrin repeat domain (ARD) of TRPV4 can reduce channel activity and further cause the osteoarthropathy related disease. Mutations in this region probably influence the constitutive activity of the channel, which mainly regulated by the binding of a small ligand such as adenosine triphosphate (ATP). These findings suggest that it is crucial to understand the fundamental mechanisms regulated by chemical ligands such as ATP binding with the ankyrin repeat domain (ARD) of TRPV4. However, how these mutations at the molecular level resulting in the related diseases are still unclear. Here we use full atomistic simulations to investigate the mutation induced conformational changes and ATP binding ability differences of TRPV4-ARD. Conformation characteristics of different mutations of TRPV4-ARD are explored. Optimal communication paths are studied to explain how a point mutation away from aim region (Finger 3) can cause a significant alteration on the conformation. We identify two molecular mechanisms through the conformation of Finger 3 and through alter the ATP binding mechanism correspondently to explain these unknowns. Our study provides fundamental insights into the mutation induced structural changes of the TRPV4-ARD and helps to explain how the mutations alter the ATP binding ability of the TRPV4-ARD.