The information stored in genes plays a huge role in directing the cellular processes underlying life, but stored information alone is inadequate to explain how cells function. Cellular forces and associated motions also play a decisive role in determining whether and when genetic information is expressed because DNA can only be copied when a chromosome is in its decompacted state and because forces and other cellular dynamics drive the transition between compacted and decompacted chromosome states. Forces are also central to the creation and migration of chromosomal density fluctuations, pockets of compaction in a nominally decompacted chromosome region (or of decompaction in a compacted region). These migrating density fluctuations can, in different scenarios, contribute both to biological function and to disfunction. Funds from this grant support Andrew Spakowitz, a Professor of Chemical Engineering and of Materials Science & Engineering at Stanford University, to develop theoretical models that will advance our understanding of how forces/dynamics impact the organization and function of chromosomes in eukaryotic cells. Spakowitz plans to achieve a multi-scale model via a staged progression of model development that describes the coupled chemical/mechanical dynamics starting at the molecular scale, he will then expand to intermediate-scale chromosome dynamics (about a tenth of a chromosome), and end with an exploration of dynamics at the scale of an entire chromosome or group of chromosomes. Forces to be modeled include constraining forces that arise from chemical bond formation between two typically distant segments of a chromosome that happen to come into proximity owing to the wiggling motion of a chromosome in the aqueous environment of a cell and which, in turn, promote chromosome compaction; thermal agitation forces (owing to collisions with water molecules) that drive chromosome decompaction; and the force exerted on DNA (by RNA polymerase) during transcription (reading of genetic information).  if successful, the project will improve our understanding of how coupled mechanical and chemical interactions at the molecular-scale drive the organizational dynamics observed at the much larger length scale of a chromosome or group of chromosomes, thereby providing insight into how forces mediate access to and use of genetically encoded information.