Software (Lattice binding models for protein-DNA assembly in chromatin; DNA condensation; signal transduction, etc...)
Basic features of DNA-protein-drug binding encountered in gene regulation include site specificity determined by the DNA sequence, binding site overlapping, competitions between different protein types or different binding modes, cooperative interactions between proteins bound to the DNA, multilayer binding and protein-assisted DNA looping (Teif, NAR 2007; Teif, BJ 2010). In chromatin, additional complex elements such as nucleosomes, remodelers and higher-order chromatin structures should be taken into account (Teif and Rippe, NAR 2009; Teif and Rippe, JPCM 2010; Teif et al, BJ 2010). Our algorithms allow calculating binding maps for protein-DNA assembly in chromatin (Teif and Rippe, BIB, 2011) taking into account cell-type specific nucleosome positioning (Teif et al., NSMB, 2012; Teif et al., Genome Res., 2014). These maps help predicting expression of genetic cis-regulatory modules (Teif and Rippe, BP, 2011).
TFnuc - Predicting transcription factor binding to chromatin
TFnuc calculates TF binding maps in the chromatin context including the possibility of partial nucleosome unwrapping:
The development of the TFnuc algorithm started in 2012 for homotypic protein-protein interactions (Teif and Rippe, 2012) and was later extended to allow arbitrary heterotypic cooperativity between nucleosomes and TFs (Teif et al., 2013). This algorithm is based on the dynamic programming approach.
Details of our algorithms are provided in the following publication:
- Teif V.B., Erdel F., Beshnova D.A., Vainshtein Y., Mallm J.-P., Rippe K. (2013) Taking into account nucleosomes for predicting gene expression. Methods. | Advance Access Online | PDF |
Examples of application of this algorithm to biological systems can be found in the following publications:
- Teif V.B., Beshnova D.A., Marth C., Vainshtein Y., Mallm J.-P., Höfer T. and Rippe K. (2014). Nucleosome repositioning links DNA (de)methylation and differential CTCF binding during stem cell development. Genome Research. 24, 1285-1295 | Pubmed | PDF | | Press release |
Beshnova D.A., Cherstvy A.G. Vainshtein Y. and Teif V.B. (2014). Regulation of the nucleosome repeat length in vivo by the DNA sequence, protein concentrations and long-range interactions. PLoS Comp. Biol. 10, e1003698 | PDF |
Predicting transcription factor binding to chromatin (transfer matrix solution)
Matrix_Unwrap - calculates transcription factor access to nucleosomal DNA taking into account the possibility of partial DNA unwrapping from the histone core octamer.
Nucleosome, the basic repeating unit of chromatin, consists of 147 basepairs of DNA that are wrapped in almost two turns around a histone protein octamer core. Because ~3/4 of the human genomic DNA is found within nucleosomes, their position and DNA interaction is an essential determinant for the DNA access of gene-specific transcription factors and other proteins. Here, a DNA lattice model was developed for describing ligand binding in the presence of a nucleosome. The model takes into account intermediate states, in which DNA is partially unwrapped from the histone octamer. This facilitates access of transcription factors to up to 60 DNA basepairs located in the outer turn of nucleosomal DNA, while the inner DNA turn was found to be more resistant to competitive ligand binding. As deduced from quantitative comparisons with recently published experimental data, our model provides a better description than the previously used all-or-none lattice-binding model. Importantly, nucleosome-occupancy maps predicted by the nucleosome-unwrapping model also differed significantly when partial unwrapping of nucleosomal DNA was considered. In addition, large effects on the cooperative binding of transcription factors to multiple binding sites occluded by the nucleosome were apparent. These findings indicate that partial unwrapping of DNA from the histone octamer needs to be taken into account in quantitative models of gene regulation in chromatin.
Details of the transfer matrix algorithm are described in the following publications:
- Teif V. B. (2007). General transfer matrix formalism to calculate DNA-protein-drug binding in gene regulation: Application to OR operator of phage lambda. Nucleic Acids Res. 35, e80.
- Teif V. B. and Rippe K. (2009). Predicting nucleosome positions on the DNA: combining intrinsic affinities and remodeler activities. Nucleic Acids Res. 37, 5641-5655. | PubMed | PDF | Supplementary Materials |
- Teif V. B., Ettig R. and Rippe K. (2010). A lattice model for transcription factor access to nucleosomal DNA. Biophys. J. 99, 2597-2607 | PDF |
Examples of the application of this algorithm to biological problems are provided in the following publications:
- Teif V.B., Kepper N., Yserentant K., Wedemann G., Rippe K. (2015). Affinity, stoichiometry and cooperativity of heterochromatin protein 1 (HP1) binding to nucleosomal arrays. J. Phys.: Condens. Matter 27, 064110 | PDF |
- Teif V. B. and Rippe K. (2011). Nucleosome mediated crosstalk between transcription factors. Phys. Biol. 8, 04400. | PubMed | PDF |
- Teif V. B. (2010). Predicting gene-regulation functions: Lessons from temperate bacteriophages. Biophys. J. 98, 1247-1256 |
DNA condensation induced by ligand binding
TwoStateDNA - Calculates ligand-induced DNA condensation in the frame of the two-state model.
In studying DNA condensation using lattice-binding approaches, we have to consider at least two coupled events: the DNA–ligand binding and DNA condensation. The "threshold degree of binding" model assumes that ligand–DNA binding is non-cooperative and does not depend on DNA compaction.In this model, DNA condenses when the degree of binding reaches a certain threshold value. On the other hand, the "two-state" models assume that DNA may be in two states, starting or condensed, and the transition between the two states is governed by different modes of ligand binding to each state. In the case of non-specific reversible binding, DNA condensation/decondensation may even be described analytically.
The notation is described in the following article:
Teif V. B. Ligand-induced DNA condensation: choosing the model. Biophys. J. 89, 2574-2587 (2005). | Free full text | Download program |
Unstructured protein binding to a multicomponent lipid membrane
Matrix_MARCKS - Calculates sequence-specific binding of an unstructured polymer to a fluid multicomponent membrane in the frame of the formalism described in the following article:
Teif V.B., Harries D., Lando D. Y. and Ben-Shaul A. (2008). Matrix formalism for site-specific binding of unstructured proteins to multicomponent lipid membranes. J. Pept. Sci. 14, 368-373. | Article PDF | Download program |