Investigation of Protein-DNA recognition using Molecular Dynamics and advanced sampling simulations

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Protein-DNA interactions are of fundamental importance for the replication and transcription of DNA as well as for all gene regulation and DNA repair processes. The aim of the project is to use computer simulations to achieve a more precise understanding of indirect DNA recognition, which is determined by the sequence-dependent DNA deformability. In addition, we also want to understand the process of protein-DNA binding by “sliding” along the DNA in molecular detail and thereby analyze the role of DNA deformability. In the first project funding phase, we managed to develop a near quantitative model of sequence-dependent DNA flexibility. This multimodal Ising model includes both the distribution of possible semi-stable conformational states of DNA and the distribution of conformations in each of these semi-stable states. The method allows for a given DNA sequence and given deformed structure to calculate the associated free energy of the deformation. In addition to this development, it was also possible to simulate at atomic resolution the sliding process for a ligand that binds in the DNA minor groove and to investigate the sliding process for a protein-DNA system using advanced sampling methods. In the second funding phase, we plan to improve and apply the multimodal Ising model to systematically calculate indirect DNA recognition for known protein-DNA complexes. Furthermore, allosteric effects of protein-DNA binding will be investigated through protein binding to DNA near a neighboring DNA site with a bound protein, which have increasingly been the focus of experimental studies in recent years. Here we expect effects with a significant range, especially for DNA segments that are subject to limited mobility at their ends, since the overall curvature and the overall twist are constant here. That is, a local change in curvature or twist (or other helical variables) necessarily causes a coupled (reverse) change in curvature or twist elsewhere, which can influence a second protein binding. DNA segments with restricted mobility occur frequently in packaged DNA (e.g. in eukaryotes) and can enable allosteric effects. In the second project phase we will also use advanced sampling methods to investigate the kinetics of the sliding processes of Ligands in DNA grooves and how it is modulated by DNA deformation.