Physical genomics: Why gene regulation is tug of war between polymer physics and biochemistry

DNA-protein interactions underlie genome activity, governing gene expression as well as the physical organisation of DNA. Until recently, DNA-protein complexes were predominantly described at atomic resolution using short DNA fragments, concealing how proteins recognise and manipulate the long, supercoiled DNA present in cells. Now single-molecule imaging and cryo-electron microscopy (cryo-EM) are showing how longer DNA sequences are recognised by proteins and computations are predicting how these elements influence larger-scale genomic structures. Here we discuss how the polymeric nature of DNA influences its atomic-level structure and dynamics, as well as the implications for DNA recognition and ultimately biological function. We emphasise how theory and simulation help interpret these effects, which are difficult to replicate using conventional experimental settings.