title: Putative binding modes of Ku70-SAP domain with double strand DNA: a molecular modeling study.
abstract: The channel structure of the Ku protein elegantly reveals the mechanistic basis of sequence-independent DNA-end binding, which is essential to genome integrity after exposure to ionizing radiation or in V(D)J recombination. However, contradicting evidence indicates that this protein is also involved in the regulation of gene expression and in other regulatory processes with intact chromosomes. This computational study predicts that a putative DNA binding domain of this protein, the SAP domain, can form DNA-bound complexes with relatively high affinities (ΔG ≈ -20 kcal mol(-1)). The binding modes are searched by low frequency vibration modes driven by the fully flexible docking method while binding affinities are calculated by the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method. We find this well defined 5 kDa domain with a helix-extended loop-helix structure is suitable to form favorable electrostatic and hydrophobic interactions with either the major groove or the minor groove of DNA. The calculation also reveals the sequence specified binding preference which may relate to the observed pause sites when Ku translocates along DNA and the perplex binding of Ku with circular DNA.
authors.affiliation: Division of Space Life Sciences, Universities Space Research Association, Houston, TX 77058, USA. Shaowen.hu-1@nasa.gov
authors.forename: Shaowen
authors.initials: S
authors.lastname: Hu
authors.forename: Janice M
authors.initials: JM
authors.lastname: Pluth
authors.forename: Francis A
authors.initials: FA
authors.lastname: Cucinotta
mesh_terms: D034961:Antigens, Nuclear / Q000737:chemistry*; D001665:Binding Sites; D003198:Computer Simulation; D004247:DNA / Q000737:chemistry*; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000737:chemistry*; D005057:Eukaryotic Cells; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D000072200:Ku Autoantigen; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D055672:Static Electricity; D013816:Thermodynamics
chemical_list: D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; D004247:DNA; D000072200:Ku Autoantigen