Unraveling the mechanistic roles of protein conformational transitions and water dynamics in ligand binding

With the support of the Chemistry of Life Processes Program in the Chemistry Division, Dr. Ao Ma from the University of Illinois Chicago is studying how proteins bind small molecules, a process both common and critical in biology and medicine. In this process of ligand binding, the conformation of proteins changes. This project aims to understand how the conformational changes are coupled to ligand movement and how the changes are also affected by water molecules. The research will use novel computational methods to reveal the step-by-step pathways and driving forces behind ligand binding. The work will help advance the understanding of enzyme function and inform the design of more effective drugs. The project will also enhance education and training through graduate curriculum development, participation in an undergraduate research program, and mentorship of high school students. The proposed research will apply the energy flow theory and generalized work functional method to compute true reaction coordinates and directly simulate the unbiased, natural dynamics of ligand binding. This approach will enable a rigorous dissection of the molecular mechanism of binding. The project will focus on two model systems: HIV-1 protease and PDZ domains, which represent the two prevalent binding paradigms-conformational selection and induced fit. Key factors that determine binding free energies and rate constants will be identified. Information will be generated on how protein conformational transitions and water dynamics collectively control ligand binding. The methods and resulting insights will advance understanding of protein-ligand interactions and support research across molecular biophysics, drug discovery, and protein engineering. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.