We acknowledge the following funding:

SFB 1027: “Physical modeling of non-equilibrium processes in biological systems”

sfblogo Gene expression in all biological cells is tightly regulated by the binding of transcription factors and by epigenetic modifications of the DNA. Importantly, gene expression and cell differentiation or cell reprogramming are triggered by suitable stimuli in a stochastic manner. Here, atomistic biomolecular simulations and coarse-grained Brownian dynamics simulations will be used to study the binding processes governing gene expression in the E.coli pap operon that is being studied experimentally in project C1. A second part of the project involves stochastic dynamics simulations to model state transitions of the gene-regulatory network centered on the pluripotency factors Oct4, Nanog and Sox2. In collaboration with project C2, we will characterize how dynamic changes of transcription factor concentrations and DNA methylation levels affect cell differentiation during the development of the early mouse embryo until the 32-cell stage.

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DFG project: “How posttranslational modifications and alternative splicing affect protein-peptide interactions”

Large-scale proteomics and transcriptomics studies have unraveled that about half of all proteins in biological cells are targets of post-translational modfications and 95% of all multi-exon genes in higher eukaryotes are alternatively spliced. Since both processes may have crucial consequences on the protein interactions involving the respective proteins, this severely complicates our understanding of the cellular protein interactome. Only few model systems have sofar been characterized in structural and thermodynamic terms. For this project, we selected two such model systems, 14-3-3 domains and PDZ domains, that both bind to hundreds of other proteins in human cells. Based on X-ray crystallographic data for the bound complexes, we will study how well molecular dynamics computer simulations can capture the influence of peptide phosphorylation on their binding to 14-3-3 adaptor domains and the influence of alternative splicing on the binding of peptides to PDZ domains. We will characterize the dynamic conformations of bound complexes, association-, dissociation-pathways and binding free energies of the peptide ligands, and the competitive binding between target peptides and small-molecule protein-protein inhibitors. This project will explore the potential and limitations of molecular dynamics simulations to contribute to the systematic proteomic mapping of the consequences of post-translational modifications and alternative splicing on the cellular protein interactome.