Exploring Ligand Binding Energy Landscape and Quantifying Specificity of Biomolecular Recognition

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Biological function encompasses a high degree of specificity, from molecules to genes to organs. Understanding biological specificity is vitally important for understanding biological function. This project is aimed at finding a theoretical guiding principle and a unified framework for investigating the specificity of biological function. The approaches to the project are threefold. First, a ligand binding energy landscape framework to uncover and quantify biological molecular specificity will be developed. This will lead to the quantification of intrinsic specificity in a unified way based on the underlying physical principles. This approach could not have been accomplished systematically before. The application of a ligand binding energy landscape constitutes a shift of thinking from conventional specificity to intrinsic specificity. Second, since specificity is an integral aspect of molecular recognition, this high specificity criterion for molecular recognition can serve as an optimization scheme. This optimization scheme will be applied to bio-molecular binding free energy estimates crucial for understanding affinity and specificity. Third, explorations will be carried out in keeping with the possibility of two-dimensional characterization of biomolecular recognition and function with both affinity and specificity instead of conventional characterization with affinity alone. In vitro and in vivo studies will be performed in close collaboration with other experimental researchers, to test the framework of specificity on biological targeting systems of Cox-2 and Ras proteins, crucial for signal transduction process and function. The major intellectual merit of this project is that the understanding of the principles and mechanisms of grand challenge problems in bio-molecular recognition specificity can be achieved through the development of a ligand binding energy landscape framework and quantification of intrinsic specificity. The principles learned can be used to develop optimization method for binding specificity, and quantitatively characterize biomolecular recognition and function with both affinity and specificity. The broader impacts of this proposal are the potential applications of the methods developed here to the ligand screening and engineering design for realizing and enhancing specific biological function. The educational aspects of the proposal will have broad impact on students and post doctorals at the interface of biology, chemistry and physics, through the integration of research and education in designing and introducing a new computational biology program, a theoretical biological physics/biophysical chemistry course, a biological physics seminar series and collaborative research training.