HOW HORMONE-RECEPTOR DNA-BINDING AFFECTS NUCLEOSOMAL DNA - THE ROLE OF SYMMETRY

Molecular dynamics simulations have been employed to determine the opt imal conformation of an estrogen receptor DNA binding domain dimer bou nd to a consensus response element, ds(AGGTCACAGTGACCT), and to a nonc onsensus response element, ds(AGAACACAGTGACCT). The structures simulat ed were derived from a crystallographic structure and solvated by a sp here (45-Angstrom radius) of explicit water and counterions. Long-rang e electrostatic interactions were accounted for during 100-ps simulati ons by means of a fast multipole expansion algorithm combined with a m ultiple time-step scheme in the molecular dynamics package NAMD. The s imulations demonstrate that the dimer induces a bent and underwound (1 0.7 bp/turn) conformation in the DNA. The bending reflects the dyad sy mmetry of the receptor dimer and can be described as an S-shaped curve in the helical axis of DNA when projected onto a plane. A similar ben t and underwound conformation is observed for nucleosomal DNA near the nucleosome's dyad axis that reflects the symmetry of the histone octa mer. We propose that when a receptor dimer binds to a nucleosome, the most favorable dimer-DNA and histone-DNA interactions are achieved if the respective symmetry axes are aligned. Such positioning of a recept or dimer over the dyad of nucleosome B in the mouse mammary tumor viru s promoter is in agreement with experiment.