engleski

Computational and spectroscopic studies of intercalators and their interaction with nucleotides

The synthesis of receptors for molecular recognition of nucleobases is very important in the research of nucleic acids. Such receptors can be used as selective/specific markers, as well as anticancer and/or antiviral drugs. In this work, the molecular modelling results are presented in combination with the spectroscopic measurements for a series of nucleobase conjugates of bisphenanthridinium as well as their non-covalent complexes with UMP and AMP. It shows how molecular modelling, particularly the long time molecular dynamics simulations (MD) can be used to rationalize the experimental results on molecules and their complexes. The molecular modelling was performed with AMBER9 suite. During the MD simulations initial, folded conformations of some molecules relaxed ; however majority of molecules remained in their folded, more or less stacked conformation with no water molecules accommodated within the two phenanthridinium rings. Obtained structures are in accord with pronounced hypochromic effect of given conjugates. Since they resemble hydrophobic cavities in which there is no water molecule, we considered them as excellent starting points for a further modelling study of the non-covalent complexes with AMP and UMP. Complexes between bisphenanthridinium – adenine derivative and UMP and AMP were built in a way to enable adenine and base from monophosphate to form the Watson-Crick type of hydrogen bonds. During the MD simulation the conformation of the complex changed and stabilized in a conformation with adenine in the stacking interaction with one phenanthridinium ring, and uracil with the other. In this conformation the hydrophobic pocket made by two phenanthridinium rings and the alkyl linker is very functional since there is no water molecule within it to compete with uracil from UMP for the hydrogen bond. The obtained results gave us explanation for experimentally determined affinity. Pyrene- guanidiniocarbonyl-pyroles (PGP) is the other set of small molecules we are studying, characterized by possibility of simultaneous formation of different binding modes. For some of them (namely NH3- conjugate, ) interact with ct-DNA and poly dA-dT nucleotides by combining intercalation with minor groove binding. To explore in more detail spectoscopicaly determined binding modes for NH3-PGP we built a possible complex, solvated it in water (TIP3P) and subjected it to MD simulation at room temperature.

molecular modelling; spectroscopy; nucleobase conjugates of bisphenanthridinium; non-covalent complexes; program Amber; PGP

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