The T <-> R transition in the insulin hexamer is an outstanding model for protein structural changes in terms of its extent and complexity: the limiting structures T-6, T(3)R(3) and R(6) have been defined by X-ray crystallography. The transition occurs cooperatively within trimers. It involves displacements of >30 Angstrom and a secondary structural rearrangement of 15% of the peptide chain between extended and helical conformations. Experimental data for the transition are plentiful, Theoretical methods to simulate pathways without constraints would never succeed with such substantial transitions. We have developed two approaches, targeted energy minimization (TEM) and targeted molecular dynamics (TMD). Previously successful in simulating the T <-> R transition of the insulin monomer, these procedures are also shown here to be effective in the hexamer, With TMD, more conformational space is explored and pathways are found at 500 kJ/mol lower energy than with TEM. Because the atoms have to meet distance constraints in sum rather than individually, a high degree of conformational freedom and independence is implied. T-6 --> T(3)R(3) and T(3)R(3) --> T-6 pathways do not coincide because the transformation is directed. One subunit enters a dead end pathway in one direction of the TMD simulation, which shows that constraint and freedom are critically balanced. The ensemble of productive pathways represents a plausible corridor for the transition, A video display of the transformations is available.