The broad, long-term objective of the project is to deepen understanding of the fundamental physical and physical chemical characteristics of the DNA molecule, both as an independent entity free in solution and as a component of the genetic apparatus. The specific aims derive from the elastic and ionic properties of DNA. The DNA polymer is stiff, which means that it offers substantial resistance to bending and twisting. In its resting state in chromatin (the genetic material of living cells), the DNA is nevertheless severely bent by interactions with proteins. Relaxation of the bent conformation can lead to structural alterations of chromatin necessary for genetic events like transcription and replication. These conformational changes, and the conditions that promote them, can be described by means of the classical theory of elasticity as well as by computer simulations. By virtue of the phosphate groups lining its surface, DNA is also a highly ionized polymer (a polyelectrolyte). Contacts between the phosphates and positively charged amino acid residues on the surface of histone proteins are thought to represent the dominant mode of DNA-protein interaction in chromatin. These interactions should be explicitly included in computer modeling in order to get a clearer idea of the influence of temperature and ionic strength on chromatin conformation. In a simpler context, DNA free in solution can interact with positively charged molecules like spermine, oligolysines, intercalating dyes, and positively charged "patches" on proteins. The polyelectrolyte effect is an important component of the interaction, and existing theory should be generalized to provide a more detailed understanding of the thermodynamics of the binding process, particularly its anticooperative aspect and its strong dependence on ionic strength. Specifically, polyelectrolyte theory needs further development to handle large ligands, and McGhee-von-Hippel theory requires further development to handle ionic interactions. Finally, there has emerged in recent years an impressive body of experimental data indicating the triggering of conformational change of polyions by the onset of counterion condensation. The theory of counterion condensation is highly developed, but coupling of condensation to polymer conformation change is poorly understood. Polyelectrolyte theory will thus be further developed to include the effect of intrapolymer attractive forces on conformation.
NIH ExPorter
NIH ExPorter