Published online 26 July 2005
Article |
Cooperative binding of DNA and CBFß to the Runt domain of the CBF
studied via MD simulations
Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland Baltimore, MD 21201, USA
*To whom correspondence should be addressed at 20 Penn Street, Baltimore, MD 21201, USA. Tel: +1 706 410 7442; Fax: +1 410 706 5017; Email: alex{at}outerbanks.umaryland.edu
Received May 27, 2005. Revised July 5, 2005. Accepted July 5, 2005.
The Runt domain (RD) is the DNA-binding region of the Runx genes. A related protein, known as core binding factor ß (CBFß) also binds to the RD to enhance RD–DNA interaction by 6- to 10-fold. Here, we report results from molecular dynamics (MD) simulations of RD alone, as a dimer in complexes with DNA and CBFß and in a ternary complex with DNA and CBFß. Consistent with the experimental findings, in the presence of CBFß the estimated free energy of binding of RD to the DNA is more favorable, which is shown to be due to more favorable intermolecular interactions and desolvation contributions. Also contributing to the enhanced binding are favorable intramolecular interactions between the ‘wing’ residues (RD residues 139–145) and the ‘wing1’ residues (RD residues 104–116). The simulation studies also indicate that the RD–CBFß binding is more favorable in the presence of DNA due to a more favorable RD–CBFß interaction energy. In addition, it is predicted that long-range interactions involving ionic residues contribute to binding cooperativity. Results from the MD calculations are used to interpret a variety of experimental mutagenesis data. A novel role for RD Glu116 to the RD–CBFß interaction is predicted.