Regulation of biological processes in the cell relies on physical interactions between biomolecules and on the resulting changes in the dynamics and conformations (shape) of the biomolecules. These processes in turn regulate relocation of biomolecules within different regions of the cell, speed up biochemical reactions, turn on and off gene expression, and aid the correct folding of other proteins. The relationship between three-dimensional structures and function of biomolecules alone is insufficient to fully explain the molecular basis of these processes. Biomolecules are not static but inherently flexible, and the role of biomolecular motions in the regulation of biological functions has remained unclear, despite an increasing number of experimental and theoretical studies. The inability to separate out the contributions of different factors to overall function is at the heart of the problem. The goal of this research project is to establish the molecular basis of the motions of biomolecules involved in biological processes. Computational tools that are developed will be publicly available and implemented into widely used open computational software for anyone to use and improve upon. The research will provide an excellent opportunity to attract and train the next generation of scientists. An advantage of the research is that it cuts across many disciplines, including chemistry, biology, physics, mathematics, and computer science, and, therefore, provides an excellent opportunity to attract students into the sciences and scientific research.
The relationship between structure and function in biomolecules is well established, however, this information is not always adequate to provide a complete understanding of the mechanism of biomolecular processes. The relationship between structure, dynamics and function in allostery and enzyme mechanisms is therefore far from being fully understood. Critical barriers to progress are the lack of fundamental understanding of the role of dynamical motions in biomolecular function and the inability to experimentally describe temporal behaviors of biomolecules at atomic resolution. The goal of this project is to establish the molecular basis of dynamical and allosteric regulation in biological systems involving cooperative substrate binding and transient protein-protein interactions in complex biomolecular assemblies. Specifically, the research uses theory and computer simulations as complementary tools to a variety of experiments, including NMR, X-ray crystallography and Surface Plasmon Resonance, to understand allosteric regulation in a multi-domain enzyme, Pin1, and a transcription factor co-regulator Pirin. The main objectives are to identify dynamical networks of residue-residue interactions that regulate function, to describe their characteristics on a quantitative level, and to explore computational approaches to access long time scale dynamics, overcoming limitations of traditional direct simulation methods. Computational investigation of the above systems in atomic detail will allow understanding of how modulation in dynamics in one region is communicated via a dynamical network of amino acid residues to a spatially distal region. The research will enhance the incorporation of biomolecular dynamics in interpreting experimental results. The research will provide the fundamental knowledge needed to establish the relationship between dynamics, structure, and function in sub-cellular processes.
This project is jointly funded by the Molecular Biophysics Cluster in the Division of Molecular and Cellular Biosciences in the Directorate for Biological Sciences and the Chemical Theory, Models, and Computational Methods Program in the Division of Chemistry in the Directorate of Mathematical and Physical Sciences.
