title: Structural Mechanism behind Distinct Efficiency of Oct4/Sox2 Proteins in Differentially Spaced DNA Complexes.
abstract: The octamer-binding transcription factor 4 (Oct4) and sex-determining region Y (SRY)-box 2 (Sox2) proteins induce various transcriptional regulators to maintain cellular pluripotency. Most Oct4/Sox2 complexes have either 0 base pairs (Oct4/Sox2(0bp)) or 3 base pairs (Oct4/Sox2(3bp)) separation between their DNA-binding sites. Results from previous biochemical studies have shown that the complexes separated by 0 base pairs are associated with a higher pluripotency rate than those separated by 3 base pairs. Here, we performed molecular dynamics (MD) simulations and calculations to determine the binding free energy and per-residue free energy for the Oct4/Sox2(0bp) and Oct4/Sox2(3bp) complexes to identify structural differences that contribute to differences in induction rate. Our MD simulation results showed substantial differences in Oct4/Sox2 domain movements, as well as secondary-structure changes in the Oct4 linker region, suggesting a potential reason underlying the distinct efficiencies of these complexes during reprogramming. Moreover, we identified key residues and hydrogen bonds that potentially facilitate protein-protein and protein-DNA interactions, in agreement with previous experimental findings. Consequently, our results confess that differential spacing of the Oct4/Sox2 DNA binding sites can determine the magnitude of transcription of the targeted genes during reprogramming.
authors.affiliation: Department of Molecular Science and Technology, Ajou University, Suwon, 443-749, Korea.
authors.forename: Dhanusha
authors.initials: D
authors.lastname: Yesudhas
authors.affiliation: Department of Molecular Science and Technology, Ajou University, Suwon, 443-749, Korea.
authors.forename: Muhammad Ayaz
authors.initials: MA
authors.lastname: Anwar
authors.affiliation: Department of Molecular Science and Technology, Ajou University, Suwon, 443-749, Korea.
authors.forename: Suresh
authors.initials: S
authors.lastname: Panneerselvam
authors.affiliation: Department of Molecular Science and Technology, Ajou University, Suwon, 443-749, Korea.
authors.forename: Prasannavenkatesh
authors.initials: P
authors.lastname: Durai
authors.affiliation: Department of Molecular Science and Technology, Ajou University, Suwon, 443-749, Korea.
authors.forename: Masaud
authors.initials: M
authors.lastname: Shah
authors.affiliation: Department of Molecular Science and Technology, Ajou University, Suwon, 443-749, Korea.
authors.forename: Sangdun
authors.initials: S
authors.lastname: Choi
mesh_terms: D001665:Binding Sites; D021901:DNA, Intergenic / Q000737:chemistry* / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D056004:Molecular Dynamics Simulation; D050814:Octamer Transcription Factor-3 / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D055748:SOXB1 Transcription Factors / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D021901:DNA, Intergenic; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors