Proteins are flexible and dynamic molecules that serve crucial functions in essentially all biological events in living cells. An important example is allostery, the coupling between ligand binding and protein conformational change. In this colloquium, I focus on elucidating the detailed mechanism of large scale (main-chain) structural changes of specific proteins where conformational flexibility is essential for function. I illustrate a theoretical model that captures the structural mechanism controlling transitions between well-folded protein conformations through two examples: (A) the calcium induced open/closed conformational change of the two calmodulin domains, and (B) the inactive/active conformational change of the N-terminal receiver domain of nitrogen regulatory protein C (NtrC) upon phosphorylation.