Molecular dynamics simulations are carried out to investigate the bind
ing of the estrogen receptor, a member of the nuclear hormone receptor
family, to specific and non-specific DNA. Two systems have been simul
ated, each based on the crystallographic structure of a complex of a d
imer of the estrogen receptor DNA binding domain with DNA. One structu
re includes the dimer and a consensus segment of DNA, ds(CCAGGTCACAGTG
ACCTGG); the other structure includes the dimer and a nonconsensus seg
ment of DNA, ds(CCAGAACACAGTGACCTGG). The simulations involve an atomi
c model of the protein-DNA complex, counterions, and a sphere of expli
cit water with a radius of 45 Angstrom. The molecular dynamics package
NAMD was used to obtain 100 ps of dynamics for each system with compl
ete long-range electrostatic interactions. Analysis of the simulations
revealed differences in the protein-DNA interactions for consensus an
d nonconsensus sequences, a bending and unwinding of the DNA, a slight
rearrangement of several amino acid side chains, and inclusion of wat
er molecules at the protein-DNA interface region. Our results indicate
that binding specificity and stability is conferred by a network of d
irect 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 fo
r the nonconsensus DNA sequence in which case the fluctuating network
of hydrogen bonds allows water molecules to enter the protein-DNA inte
rface. We conclude that water plays a role in furnishing DNA binding s
pecificity to nuclear hormone receptors.