The energetics of amyloid fibrillar aggregation of beta-lactoglobulin (beta LG) following incubation at high temperature and acid pH Was studied by differential scanning calorimetry in the presence of Cu2+ or Fe3+ cation; and without any metal. Cu2+ and metal-free protein solutions showed a distinct exothermic response that disappeared almost completely when the Fe3+ molar concentration was ten times greater than the beta LG concentration. Thioflavin T fluorescence studies in solution and atomic force microscopy analysis of the deposit left on flat mica substrates by heat-incubated beta LG solutions correlated the absence of exothermic response of Fe3+-beta LG solutions with a lack of fibril production. In contrast, abundant fibril deposits were observed for Cu2+-beta LG solutions, with a rich polymorphism of multistrand fibrillar structures. Electron paramagnetic resonance revealed that Fe3+ permanently binds to beta LG in the aggregate state whereas Cu2+ plays a catalytic role without binding to the protein. We propose that Fe3+ inhibits fibril production after binding to a key region of the protein sequence, possibly interfering with the nucleation step of the fibrillation process and opening a nonfibrillar aggregation pathway: These findings suggest that transition metal ions can be utilized to effectively modulate protein self assembly into a variety of Structures with distinct morphologies at the nanoscale level.