Free-energy landscapes of protein domain movements upon ligand binding

The conformation and functions of proteins are closely linked, and many proteins undergo conformational changes upon ligand binding. The X-ray crystallographic studies have revealed conformational differences in proteins between the liganded and unliganded states. Currently, the conformational transitions that originate in the ligand binding are explained on the basis of two representative models, the induced-fit and preexisting equilibrium dynamics models. However, the actual dynamics of the proteins remain ambiguous. Though these two models are the extreme ones, it is important to understand the difference between these two, particularly in structural biology and medicinal chemistry studies. Here, we clarified the difference in the mechanisms responsible for the conformational changes induced in two proteins upon ligand binding by examining computationally determined free-energy profiles of the apo- and holoproteins. The lysine/arginine/ornithine-binding protein and maltose/maltodextrin-binding protein were chosen as the target proteins, and the energy profiles were generated by a molecular simulation approach. Our results revealed that fluctuations in the apo state and protein-ligand interactions both play important roles in conformational transition, and the mechanism is highly influenced by the fluctuations in the apo state, which are unique to a particular structure.