Probing the Structure/Function/Dynamics Relationship in Biomolecular Complexes with Multiscale Computational Techniques

Project Summary: Over the last two decades, enabled by progress in synchrotron radiation techniques, molecular biology methods, and computational resources, there has been tremendous progress in determining the conformations of biomolecules that has led to deep structural and functional insights. But there is another dimension to biological function, namely dynamics, which is, as yet, underexplored. This has created a serious blind spot that inhibits progress towards a full understanding of macromolecular functions and biological processes. The broad objective of this proposal is to utilize and develop computer simulations that address this deficiency in knowledge by rigorously modeling biomolecular dynamics to increase our understanding of biological processes. More specifically, we will pursue three interrelated projects. First, we will determine how chromatin remodeling factors influence the dynamics of nucleosomes and chromatin fibers as a means of epigenetic gene regulation. Second, we will examine the mechanisms of key virulence factors in bacteria, including how they scagence iron from hosts and how they defended themselves from peptidomimetics. Finally, we will develop computational methods that more effectively model the results of solution small angle X-ray scattering experiments for diverse biomolecular complexes. Completion of these studies will reveal intricate details about the relationship between the structure, function, and dynamics of multicomponent biomolecular complexes across a vast range of time and length scales. Furthermore, the synergy between the scientific goals, as well as the computational methods and strong experimental collaborations in each of these projects, will foster new opportunities and areas of scientific inquiry that the MIRA award will allow us to pursue. Overall, this work will address a series of fundamental gaps in knowledge for critical biological processes, and will lay the foundation for future studies that will improve the treatment and prevention of human ailments.