Molecular recognition is one of the key issues in modern molecular biology. Although rigid and semi-rigid binding has been extensively explored, flexible binding with large conformational changes which is often found in the process and function of the cell is not well understood yet. The objective of this project, jointly supported by Molecular Biophysics in the Division of Molecular and Cellular Biosciences and the Theoretical and Computational Chemistry Program in the Chemistry Division, is to establish a theoretical framework to understand the fundamental mechanism (how flexibility might help recognition) and quantify the kinetic paths of the flexible binding. The study of the flexible binding will be carried out in three integrated steps: First, a theoretical framework for flexible binding will be established to understand the role of flexibility on the thermodynamic properties. Second, a path integral formalism will be developed to quantify the kinetic binding paths, understand the roles of flexibility and folding on the kinetics of flexible binding, and answer the questions on the fundamental mechanism of binding such as which set of kinetic paths the binding will be more likely to take. Third, the question of how the flexibility helps the recognition at the atomic level will be explored. The major intellectual merit of this research is to understand the fundamental mechanisms of flexible bio-molecular recognition through the development of a new theoretical framework and identification of kinetic paths. The principles learned can be used to guide the atomic level kinetic path simulations of specific recognition complexes, overcome the conventional computational bottleneck and explore the dynamic functions.
The educational aspect of the project will have broad impact on students from all over the world pursuing interdisciplinary studies at the interface of biology/chemistry/physics, starting with the students in the U. S., China, and Brazil. The research and education efforts will be integrated. This includes designing interdisciplinary courses and curricula on bio-molecular recognition and computational biology for undergraduate and graduate students; writing a book on energy landscapes of bio-molecules; linking the methodologies developed in this research to applications in industry; and developing an international (China and Brazil) collaborative research and education program on bio-molecular recognition.
