The present invention provides methods for determining the structure and/or function of one or more domains of a cation-dependent (and preferably calcium-dependent) polypeptide (particularly a calcium-dependent enzyme, which may be a protease such as calpain) in the presence of one or more cations. The invention further provides methods for identifying a ligand having the ability to bind to one or more ligand-binding domains (LBDs) of a cation-dependent (and preferably calcium-dependent) polypeptide, and ligands identified by these methods. The invention also provides methods of treating or preventing physical disorders in animals using these ligands.