|
Despite the astonishing amount of information now known about the sequential makeup and spatial organization of many genomes, there is much to learn about how the vast numbers of bases in these systems contribute to their three-dimensional architectures and workings. The structures of DNA and RNA contain information that dictates the observed arrangements of bases within these molecules and the susceptibilities of different base sequences to interactions with proteins and other molecules. Our group is developing software to analyze the spatial and energetic codes within known DNA and RNA structures and is using these data in studies of larger nucleic acid systems. By representing the DNA or RNA bases and base pairs as sets of geometric objects, we can capture natural the spatial deformabilities of free DNA or RNA as well as the structural details of ligand-bound interactions. This approach leads to results that can be directly linked to genetic processing at the macromolecular level. For example, DNA elements that regulate gene expression often lie far apart along genomic sequences but come close together during genetic processing. The intervening residues form loops, mediated by proteins, which bind at the sequentially distant sites. We relate the computed looping propensities to looping propensities derived from biological and physical studies. We are also collecting the simulated structures in databases of three-dimensional loop models that can be used as starting points in the determination of structures consistent with NMR and other local spectroscopic measurements and subsequently refined with these high-resolution data. The approach is general and can be applied to any known protein-mediated DNA looping systems as well as to the design of novel DNA constructs, such as the three-dimensional origami formed by looping DNA between carefully spaced four-way junctions.
|
Sign in
to view more information about this project.
