Molecular Dynamics Study of Hormone Receptors Binding DNA and Hormones

"Molecular dynamics (MD) simulations are employed to examine the dynamic structural properties of modified DNA, binding of the estrogen receptor to specific and non-specific DNA, and binding/unbinding of hormones to/from retinoic acid receptor and thyroid hormone receptor. In the DNA dodecamer, d(CGCGAATTCGCG), two Adenine residues, individually or jointly, were replaced with the 2 '-deoxy-7-(hydroxymethyl)-7-deazaadenosine (hm7c 7dA) analogue. The simulations show that the incorporation of the analogue appears to affect neither the overall DNA structure nor its hydrogen-bonding and stacking interactions when only one individual base is replaced by the analogue. These data suggest that the analogue should be a good mimic of the ""ordered"" water molecules observed in DNA and protein-DNA complexes. MD simulations of the estrogen receptor DNA binding domain bound to consensus and non-consensus DNA, revealed differences in the protein-DNA interactions, a bending and unwinding of the DNA, a slight rearrangement of several amino-acid side-chains and inclusion of water molecules at the protein-DNA interface region. These results indicate that binding specificity and stability is conferred by a network of direct and water mediated protein-DNA hydrogen bonds. For the consensus sequence, the network involves three water molecules, residues Glu25, Lys28, Lys32, Arg33 and bases of the DNA. For the non-consensus DNA sequence, the fluctuating network of hydrogen bonds allows water molecules to enter the protein-DNA interface. We conclude that water plays a role in furnishing DNA binding specificity to nuclear hormone receptors. Three possible binding/unbinding pathways of the retinoic acid (thyroid) hormone to/from retinoic acid receptor (thyroid hormone receptor) were explored using Steered Molecular Dynamics simulations. Unbinding was induced on a time scale of 1 ns by applying external forces to the hormone. The simulations suggest that the hormone may employ one pathway for binding and an alternative ""back door"" pathway for unbinding."

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Chemical Physics

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2015

Author dc:creator

• Kosztin, Dorina Carmen

Contributors dc:contributor

• Schulten, Klaus

• Biology, Molecular

Language dc:language

eng

Identifier

(MiAaPQ)AAI9921706

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/84436