title: Cooperative binding of DNA and CBFbeta to the Runt domain of the CBFalpha studied via MD simulations.
abstract: The Runt domain (RD) is the DNA-binding region of the Runx genes. A related protein, known as core binding factor beta (CBFbeta) 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 CBFbeta and in a ternary complex with DNA and CBFbeta. Consistent with the experimental findings, in the presence of CBFbeta 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-CBFbeta binding is more favorable in the presence of DNA due to a more favorable RD-CBFbeta 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-CBFbeta interaction is predicted.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland Baltimore, MD 21201, USA.
authors.forename: Bahru
authors.initials: B
authors.lastname: Habtemariam
authors.forename: Victor M
authors.initials: VM
authors.lastname: Anisimov
authors.forename: Alexander D
authors.initials: AD
authors.lastname: MacKerell
mesh_terms: D000596:Amino Acids / Q000737:chemistry; D001665:Binding Sites; D003198:Computer Simulation; D050657:Core Binding Factor alpha Subunits; D050660:Core Binding Factors; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D009363:Neoplasm Proteins / Q000737:chemistry; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000596:Amino Acids; D050657:Core Binding Factor alpha Subunits; D050660:Core Binding Factors; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D050656:Transcription Factor AP-2; D014157:Transcription Factors; C406688:core binding factor alpha; D004247:DNA