INTERACTION OF HUMAN SRY PROTEIN WITH DNA - A MOLECULAR-DYNAMICS STUDY

Molecular dynamics simulations have been conducted to study the intera ction of human sex-determining region Y (hSRY) protein with DNA. For t his purpose, simulations of the hSRY high mobility group (HMG) domain (hSRY-HMG) with and without its DNA target site, a DNA octamer, and th e DNA octamer alone have been carried out, employing the NMR solution structure of hSRY-HMG-DNA complex as a starting model. Analyses of the simulation results demonstrated that the interaction between hSRY and DNA was hydrophobic,just a few hydrogen bonds and only one water mole cule as hydrogen-bonding bridge were observed at the protein-DNA inter face, These two hydrophobic cores in the hSRY-HMG domain were the phys ical basis of hSRY-HMG-DNA specific interaction. They not only maintai ned the stability of the complex, but also primarily caused the DNA de formation. The salt bridges formed between the positive-charged residu es of hSRY and phosphate groups of DNA made the phosphate electroneutr al, which was advantageous for the deformation of DNA and the formatio n of a stable complex, We predicted the structure of hSRY-HMG domain i n the free state and found that both hSRY and DNA changed their confor mations to achieve greater complementarity of geometries and propertie s during the binding process; that is, the protein increased the angle between its long and short arms to accommodate the DNA, and the DNA b ecame bent severely to adapt to the protein, although the conformation al change of DNA was more severe than that of the hSRY-HMG domain. The sequence specificity and the role of residue Met9 are also discussed. (C) 1998 Wiley-Liss, Inc.