Exploration of Free-Energy Profiles With Conformational Changes of Proteins

Abstract

Under physiological conditions, proteins fluctuate around their native state and often undergo conformational changes on interacting with ligands. Thermal fluctuations are critical to the dynamics of nanoscale structures like proteins, and conformational changes can stabilize the binding energy of these molecules; therefore, both these factors are crucial for the retention of protein function. Recently, X-ray crystallographic studies have revealed conformational differences between the liganded and unliganded states of proteins. The conformational transition induced in proteins upon ligand binding can be explained by 2 representative models, the induced-fit model and the preexisting equilibrium dynamics. However, it remains unclear as to whether these models appropriately describe the actual dynamics of proteins.Here, we performed molecular dynamics (MD) simulations for the lysine/arginine/ornithine (LAO)-binding protein and the maltose-binding protein (MBP). We used the umbrella sampling approach to examine the free-energy profiles governing the conformational changes induced in these proteins upon ligand binding. The conformational transition mechanisms of LAO-binding protein and MBP are believed to differ, being characterized by the preexisting equilibrium dynamics and the induced-fit model, respectively. However, our results revealed that the conformational transition mechanism of LAO-binding protein is based on a combination of the preexisting equilibrium dynamics and the induced-fit model, rather than solely on the former, while the mechanism of MBP is based mainly on the induced-fit model. And it was also suggested that the fluctuations in the apo state are important for the conformational changes and the protein function in both of these proteins.