A molecular dynamics study of hormone receptor-DNA binding
Bishop, Thomas Connor
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Permalink
https://hdl.handle.net/2142/21505
Description
Title
A molecular dynamics study of hormone receptor-DNA binding
Author(s)
Bishop, Thomas Connor
Issue Date
1996
Doctoral Committee Chair(s)
Schulten, Klaus J.
Department of Study
Chemistry
Discipline
Chemistry
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
Biology, Molecular
Chemistry, Biochemistry
Biophysics, General
Language
eng
Abstract
Molecular dynamics simulations are utilized to investigate the binding of hormone receptors to DNA. The hormone receptors constitute a family of gene regulatory proteins that can be divided into two subfamilies based on the sequence of DNA to which a receptor binds with high affinity. The glucocorticoid receptor subfamily binds with high affinity to ds(AGAACA), and the estrogen receptor subfamily binds with high affinity to ds(AGGTCA). We have conducted a set of simulations representing each hormone receptor subfamily based on available X-ray crystallographic structures of a glucocorticoid receptor DNA binding domain dimer/DNA complex and an estrogen receptor DNA binding domain dimer/DNA complex. Each set of simulations consisted of at least three individual simulations: the dimer interacting with a consensus DNA sequence, the dimer interacting with a non-consensus DNA sequence, and simulations conducted for experimental control. For each simulation an explicit solvation shell was utilized. Analysis of the simulations in terms of atomic interactions investigates contacts between the protein and the DNA to determine the basis of sequence specificity. We find that three amino acids and two base-pairs are sufficient to create a hydrophobic protein-DNA interface for the glucocorticoid receptor subfamily and a hydrophilic protein-DNA interface for the estrogen receptor subfamily. Analysis of simulations in terms of molecular structure investigates conformational changes in the protein-DNA complexes that bend the DNA. The bend is projected onto two perpendicular planes. In one plane the dimer is on the convex surface of the bend, i.e., the DNA bends away from the protein. In the other plane two symmetric bends in the DNA are oriented in opposite directions and tend to cancel each other resulting in a displacement of the DNA helical axis. The conformation of the DNA induced by the receptor dimer is similar to the conformation of nucleosomal DNA in a region about the nucleosome axis of dyad symmetry. We suggest that binding of a receptor dimer to nucleosomal DNA changes the positioning of DNA on the nucleosome to align the center of the receptor dimer/DNA complex with the nucleosome dyad. This change in positioning explains the rearrangement of nucleosome structures that naturally occurs upon the binding of receptor to chromatin and represents an essential part of the mechanism of gene regulation by hormone receptors.
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