Lester F. Harris, Principal Investigator
Leonard S. Schultz, Co-Principal Investigator

Dynamic Simulations of Solvated Protein/DNA Complexes

a. A computer model of one glucorticoid receptor dimer in complex with a glucorticoid response element from the mouse mammary tumor virus 5′ long terminal repeat nucleosome DNA in a supercoiled conformation. b. The complex viewed along the DNA nucleosome axis shown in a water box for PME periodic boundary solvated molecular dynamics simulations.		a. A ribbon structure of the androgen receptor protein dimer in complex with a 29 bp DNA sequence containing an androgen response element. b. The complex shown with a water box for PME periodic boundary solvated molecular dynamics simulations.

These researchers are conducting experiments investigating the mechanism(s) of a genetic switch controlled by deoxyribonucleic acid (DNA) regulatory proteins. They are interested in steroid hormone receptor protein interaction with DNA in the pathogenesis of breast cancer. The researchers have previously reported on a mechanism describing how these DNA regulatory proteins recognize and bind to their specific sites on DNA. They are conducting Particle Mesh Ewald (PME) periodic boundary molecular dynamics simulations in solvent to investigate hydrogen bonding, van der Waals, and electrostatic interactions between amino acids of the of the DNA regulatory proteins and nucleotides of their cognate DNA biding sites. They have constructed separate large models of the 434 cI repressor and Cro proteins in complex with all three of the operators—OR1, OR2, and OR3—involved in regulation of a genetic switch. The models will allow the researchers to complete their study of the prokaryotic genetic switch regulating lytic/lysogeny expression in the 434 bacteriophage.

Using a high-resolution crystal structure of a nucleosome core particle of chromatin, the researchers have developed an exact nucleosome model of the 5′ long terminal repeat nucleotide sequence upstream of the mouse mammary tumor virus genome. This genome contains well-characterized DNA binding sites for steroid hormone receptor proteins. The model will allow the researchers to study eukaryotic regulatory elements in their natural context to develop a better understanding of the requirements for controlling expression of transfected genes.

The researchers have also constructed a model of the androgen receptor protein in complex with its cognate DNA binding site. This model will aid in the study of wetwork experiments in prostate cancer research.

Finally, the researchers are computing the PME periodic boundary solvated dynamic simulations on several other steroid receptor/DNA complexes. These studies include DNA-containing various hormone response elements (cognate and non-cognate) in complex with most members of the steroid receptor superfamily of proteins, particularly the estrogen, glucocorticoid, retinoic acid, and progesterone receptors.