The central aim of this project is to develop computational models capable of describing the structure, dynamics and ultimately the function of DNA in the cell nucleus. In the cell, as much as a meter of DNA can be packaged into a dense aggregate that measures only a micrometer. This aggregate consists of a DNA protein complex that is referred to as chromatin, and its structure is central to gene regulation. Chromatin exhibits a truly hierarchical structure, in which modifications at the smallest length scales influence structure and dynamics over much longer distances. Importantly, deregulation, or "misreading," of the underlying DNA has been implicated in numerous diseases, including cancer. Despite the inherent function of chromatin, its structure in the cell nucleus largely remains a mystery. This work will seek to resolve that structure, and potentially shed light on the origin and spread of various genetic disorders. The project will be carried out by the principal investigator and graduate students. In addition to receiving advanced training on the modeling and research aspects of the project, these students will receive communications training and will participate in programs conceived to provide local communities with an understanding of the role chromatin plays in our daily life. As such, this work will offer an opportunity to engage young students in future scientific careers.
This work promises to answer important biophysical questions regarding the emergence of large scale biological behavior from small scale molecular interactions. The proposed comprehensive model of chromatin will link one-dimensional primary structure and dynamics to three-dimensional secondary and tertiary structure and motion. It will rely on existing experimental data pertaining to multiple length scales, and it will couple top-down and bottom-up modeling design approaches. To do so, a strategy will be adopted in which advanced sampling techniques are used to extract free energy differences between different experimentally-proposed chromatin configurations. A guiding principle in the development of the model will be to gain the ability to span the range of length and time scales that are necessary to understand chromatin structure and dynamics. It is anticipated that, when completed, the proposed model will yield an unprecedented view of the genome and lead to hitherto unavailable insights into how genetic mechanisms are altered by external challenges. An important aspect of the project will be to examine the role of histone and DNA modifications, such as acetylations, on higher-order chromatin structures. More generally, the three-dimensional, molecular models envisaged in this project will be the first of their kind, and will become an important tool for studies of cellular DNA.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
