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Modeling the interaction between a non-specific DNA-binding peptide and canonical B-DNA (Master thesis)

Παναγόπουλος, Ευάγγελος-Μάριος/ Panagopoulos, Evangelos-Marios

This thesis investigates the interactions between a 12-mer peptide (SVSVGMKPSPRP) and canonical B-DNA, focusing on the mechanisms underlying its non-specific binding, using a combination of advanced computational approaches. For this purpose, 100 potential peptide conformations, which were available through folding molecular dynamics simulations, were docked to a canonical B-DNA molecule using the HDOCKlite tool. The docking energy scores were analyzed, identifying five promising conformations that exhibited significant energy drops. Further docking experiments were conducted using HADDOCK and PyDockDNA tools to refine these models, with the resulting complexes visualized using the Pymol program. Detailed structural analysis revealed the 3 most efficient models that demonstrate the interactions that are formed in the peptide-DNA complex. The binding mechanism was found to be dominated by electrostatic interactions, particularly between the peptide's positively charged residues and the DNA backbone's negatively charged phosphates. Hydrophobic interactions and Van der Waals forces stabilize further the models, along with hydrogen bonding which seem to play a less significant role. While the docking tools did not converge on a specif ic binding site, they consistently identified the interactions that drive the peptide's nonspecific binding to B-DNA. The study highlights the limitations of simulating the peptide in its free form (in the absence of the DNA molecule) and emphasizes the need for future research to consider the dynamic nature of the peptide-DNA complex and also the need for experimental confirmation of the results.