How protein dynamics affects ligand dissociation?
Research from Professor Hak Sung Kim and Dr. Moon Hyung Seo demonstrated a regulation mechanism of a ligand dissociation in the recognition process between biomolecules and proteins in vivo. This research was published online in March 18th in “Nature Communications.”
Proteins, such as enzymes, antibodies and hormones, play the most important role in controlling and maintaining biological activity through synthesis, catalysis, signal transduction or immune responses through specifical interactions with diverse biomolecules. As many proteins are not static, but dynamic in nature, they have various conformational substrates. As presented in Nature Chemical Biology last year, the group’s research first elucidated the molecular recognition mechanism of a protein showing conformational dynamics. The research group used a technique called single-molecule FRET to show how protein structures change as a ligand binds in-real time.
Recently, it is of significance to figure out the interplay between the conformational dynamics and functions of proteins. What are the factors that trigger dissociation of a ligand from a protein? This is a critical question. To address this issue, the research group constructed diverse mutants of maltose binding protein (MBP) by altering the residues at a particular site. This site is called the hinge site and keeps the interface unchanged. Specifically modified proteins (mutants) were subjected to single-molecule FRET analysis to track conformational changes in real-time. They showed that binding affinity is mainly affected by the opening rate of the protein. The group noted that during the process of biomolecule recognition by a protein, the binding affinity between the two molecules is not only dependent on the chemical properties of the interacting surface, but also on the intrinsic conformational dynamics of a protein (Figure 1). Through this study, the key principle that regulates binding affinity between a protein and a ligand was revealed, expecting that it makes a significant contribution to a clearer understanding of how conformational dynamics regulate protein function.
The binding affinity is key in determining the function of a protein in many biological processes. The results offer the possibility of controlling more accurately the function of proteins; therefore it is anticipated to develop more effective therapeutic agents and a detailed biological understanding of the events in various diseases such as cancer and diabetes.