Dorina Kosztin, Thomas C. Bishop, and Klaus Schulten.
Binding of the estrogen receptor to DNA: The role of waters.
Biophysical Journal, 73:557-570, 1997.
(PMC: 1180957)
KOSZ97A
Molecular dynamics simulations are carried out to investigate the binding of the estrogen receptor, a member of the nuclear hormone receptor family, to specific and non-specific DNA. Two systems have been simulated, each based on the crystallographic structure of a complex of a dimer of the estrogen receptor DNA binding domain with DNA. One structure includes the dimer and a consensus segment of DNA, ds(CCAGGTCACAGTGACCTGG); the other structure includes the dimer and a nonconsensus segment of DNA, ds(CCAGAACACAGTGACCTGG). The simulations involve an atomic model of the protein-DNA complex, counterions and a sphere of explicit water with a radius of 45 Å. The molecular dynamics package NAMD was used to obtain 100 ps of dynamics for each system with complete long range electrostatic interactions. Analysis of the simulations revealed differences in the protein-DNA interactions for consensus and non-consensus sequences, 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. Our results indicate that binding specificity 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 Glu-25, Lys-28, Lys-32, Arg-33 and bases of the DNA. The binding differs for the non-consensus DNA sequence in which case the network involves five water molecules . We conclude that water plays a role in furnishing DNA binding specificity to nuclear hormone receptors.
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