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Published on: 4月 15, 2026
Complexation of a protein and the ligand induces biological functions and hence its control is the key for drug discovery. X-ray crystallography can determine the static structure in an atom-level resolution, but the dynamic conformational change as well as a small local fluctuation makes it difficult to rationally design the best ligand for a particular target. There is an urgent need to disentangle the complexity of complex formation not only for protein-ligand but also protein-protein interaction.
The theoretical basis of protein-ligand complex formation was rationally proposed on protein folding in the late 1980s to the early 1990s.1),2),3),4) But the concept of current theories, conformational selection (CS) and induced fit (IF) were postulated around 1960.5),6)
CS is a process of ligand binding when the protein has a requisite conformation. Thus the trigger of complexation is driven by conformational change of the protein and the ligand binding stabilize the conformation.
On the other hand, IF is a process of inducing protein’s conformational change to fit the ligand by a contact with the ligand itself. The ligand controls the conformation of the target to form the stable complex.
The comprehensive review on theoretical models of CS and IF in 2014 schematically describes the relation of states of the protein and the ligand binding.7) Four-state model is often described, in which both CS and IF are involved in protein-ligand interaction.
The process of complexation is complicated. Basically, the model consists of four states: unbound ground state, unbound and bound intermediate state, and bound ground state. Simplistically, the unbound ground-state conformation would change the structure by thermodynamic process to become an intermediate conformation. Then the ligand binds to the protein and it triggers conformational change to the final ground state.
The situation is not straightforward in macromolecule interactions. Proteins of high flexibility would dynamically change its structure and the minor conformation could be selected by the ligand to drive a conformational change for overall high stability. The dynamics of interaction could also drive the complex to reverse direction as well. The four-state model is still a simple but represents the intermingle of CS and IF in protein interaction.
NMR relaxation dispersion is a powerful tool for the investigation of biological process since its resolution is micro seconds to milli seconds and it is a prevalent time course. This paper8) tested NMR relaxation dispersion to evaluate the importance of CS and IF as a case study. The author took galectin-3 carbohyderate-bindng domain as the model and used lactose as the ligand. The research showed that CS and IF acts as a trigger of complexation in this particular case and NMR relaxation dispersion successfully separated the CS, IF and four-state process.
The author concluded that the result would provide an enriched view of CS an IF and extend the understanding of protein- ligand complexation process. It is true but what is more significant is that they demonstrated NMR could disentangle the complexity of macromolecule interactions. Of course, biological process could be much faster and the resolution of NMR is not suitable in that case. But still NMR relaxation dispersion would play an invaluable role for the understanding of protein-ligand and protein-protein interaction dynamics.