Book of Abstracts: Albany 2005
Molecular Modeling of a 30 Amino Acid Linker Connecting the DNA Binding Domain (DBD) and Ligand Binding Domain (LBD) of the Glucocorticoid Receptor (GR) Protein Using Secondary Structure Prediction, Model Building, Conformational Space Annealing, Energy M
We have conducted extensive molecular dynamics simulations to study the interactions of the GR DNA binding domain (DBD) in complex with the mouse mammary tumor virus glucocorticoid response element. Currently the X-ray and NMR structural determinations of both the GR DBD and GR ligand (steroid) binding domain (LBD) are available, but coordinates for a 30 amino acid sequence that connects the DBD and LBD are unavailable. In order to construct a complete model of the GR including both DNA and ligand binding domains it is necessary to build a model of the 30 amino acid linker. We are currently working with a large nucleosome model for the GRE and studying protein-protein interactions between both monomers of the GR DBD dimer. We are also interested in the protein-protein interactions between the monomers of the GR LBD dimer as well. By using secondary structure prediction, model building, conformational space annealing, energy minimization and finally particle mesh Ewald (PME) solvated molecular dynamics; it is our goal to construct a putative model of the GR protein that can be used in simulations of GR in complex with nucleosome DNA (See Figure 1).
Figure 1: A computer model of glucocorticoid receptor (GR) protein DNA binding domain (DBD) in complex with nucleosome DNA consisting of a mouse mammary tumor virus (MMTV) DNA sequence with five glucocorticoid response elements. The GR steroid binding domain (LBD) is shown docked to the DBD in an orientation based on structural and charge complementarity. The approximate locations of the missing linker amino acids are indicated by the white dashed lines. The histones have been removed from the nucleosome DNA for visual clarity.
Lester F. Harris*
Hickok Memorial Cancer Research Laboratory