Theoretical Studies of Protein-Ligand Binding Energetics and Kinetics

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9808202 Sharp This research is directed at understanding the physical and chemical basis of specific binding of proteins to their ligands. The goal is to answer two key questions that play an important part in the biological function of proteins: i) How do the structure and chemical properties of the protein and ligand result in favorable energetics (high affinity) for the correct binding complex? ii) How do the structure and chemical properties control the dissociation kinetics under applied forces. The binding free energy will be calculated using a combination of molecular mechanics and finite difference Poisson-Boltzmann methods. Changes in internal translation and ratational entropy in the complex will be computed from fluctuations in the structure obtained from molecular dynamics simulations. Brownian dynamics will be used to study the dissociation kinetics of protein-ligand systems in the presence of intrinsic and extrinsic (mechanical) forces. Solvent screened forces that affect the dissociation will be included using a finite difference Poisson-Boltzmann approach. Brownian dynamics simulations will be used to understand the relationship between structure and dissociation kinetics of protein-ligand interactions that do or do not mediate cell adhesion. The ability to calculate and eventually predict how tightly a protein binds other molecules (ligand) may be termed the "binding affinity problem", and it ranks in importance with other major problems in modern structural biology such as the "protein folding problem", and the basis of catalytic activity in proteins. The ability to understand how the structure of a protein enables it to bind a specific target molecule will increase our understanding of many biological events at the molecular level such as antibody-antigen-affinity, antigenicity, specificity in signal transduction pathways, the function of inhibitors, etc. Applications of research on the binding problem also include protein engineering. Understanding the mechanism an d rate at which proteins become unbound from their ligands in the presence of forces is important in understanding the different adhesion behaviors shown by cells. The ability to simulate dissociation kinetics will shed light on the relationship between molecular structure, dissociation and biologically important functions such as cell adhesion.