Molecular Dynamics Study of Hormone Receptors Binding DNA and Hormones

118 p.Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 1999.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.U of I OnlyRestricted to the U of I community idenfinitely during batch ingest of legacy ETD