engleski

Molecular modeling of new permanently charged phenanthridinium-nucleobase conjugates in complexes with double stranded polynucleotides

Small molecules targeting DNA/RNA have attracted significant scientific interest due to the medicine, biochemical and biological implications of such molecular recognition events. Most often these small molecules rely on the dominant non-covalent binding mode for their interacion with double stranded (ds) DNA/RNA (e.g. intercalation, minor groove binding). The combination of different binding modes within one molecules as well as additional steric and structural features controlling three-dimensional recognition drew some attention over the last few years with the aim of developing new more selective drugs or biochemical markers as well as research tools on a molecular level. Since many of the antitumor drugs act by modifying (i.e. alkylating) nucleobases in DNA, molecules that bind specifically at such lesions and inhibit the DNA repair system may potentiate the action of antitumor drugs. In this work we shall present our molecular modelling results in combination with spectroscopic measurements for a series of new permanently charged phenanthridinium-nucleobase conjugates in complexes with polynucleotides. Specifically, the complexes with double stranded DNA (poly dAdT – poly dAdT) and double stranded RNA ( poly AH+) were studied. Since here we are dealing with protonated adenine in RNA, we had to implement a special procedure of parameterization. The calculations required for parametrization of the nucleotide with protonated adenine were carried out using the Gaussian033 program at the HF/6-31G(d) level of theory. The molecular modelling was performed with AMBER101 suite. AMBER ff99SB2 and GAFF1 force field were used to parameterize molecules.

molecular modelling; AMBER; phenanthridinium conjugates; DNA; RNA

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