UC Riverside

Molecular recognition and functional dynamics are fundamental in chemical processes, often seen in those chemical and biological systems. The molecular recognition process guides molecular species with preferential binding and unbinding events via physical differentiation and complementarity. Many experimental techniques show promising results, yet limitations in studying such fundamental process at a molecular level. With the advanced and rapid development of computational technology and mathematical algorithms, molecular modeling has become an effective and powerful tool in studying molecular recognition processes, such as investigating the interactions between molecular species and understanding the biological dynamic processes, making it significant and indispensable contributions to modern medicinal chemistry, biology, and drug development. The state-of-the-art techniques of computational chemistry and molecular modeling can be employed to study a wide range of chemical and biological systems of interest, which allow people to understand the structural-functional-relation in detail at a microscopic view, and gain chemical/biological information which deem to be challenging by experimental measurements. The work in this dissertation focuses on modeling the recognition processes and protein functional dynamics of biomolecules in different biological systems using multiple computational approaches, such as homology modeling, molecular docking including protein-protein and protein-ligand docking, structural-based alignment and superposition, molecular dynamics (MD) and Brownian dynamics (BD) simulations, enhanced samplings, and MM/GB(PB)SA-based energy calculations. We also apply various post-analysis tools to understand the systems of interest’s dynamic nature and motions in details in this dissertation.A strong focus in two projects describe here use MD simulations to demonstrate physical and chemical principles that govern ligand’s effectiveness in the complex and understand the ligand binding affinity. One project focuses on applying MD simulations to investigate and demonstrate the protein’s functional dynamics, which deem to link to its characteristic features in the disease. In addition, diffusional association and dissociation binding events between receptor and substrate are also studied in this dissertation project. We apply BD simulations to model such events with over microseconds to millisecond timescale. A computational efficient BD simulation software developed in our group is introduced and applied to study different structural features that affects the substrate binding efficiency.