Simulation of the interactions between Tröger bases and DNA

Clarisse G Ricci,Paulo A Netz

doi:10.1590/s0103-50532012000700019

Abstract

Tröger bases are a class of molecules that, due to its geometry, bind enantioselectively to DNA. Molecular dynamic simulations were performed with levorotatory isomers of proflavine and phenanthroline substituted Tröger bases. Starting with the bases docked in DNA, the distortions they promote in the double helix were investigated in two possible modes: intercalation and minor groove binding. In the intercalation complexes, they presented long residence times and distorted the double helix leading to partial unwinding and to non-canonical values of some backbone angles. In the minor groove complexes, they displayed high mobility, leading to a change in the binding mode, interacting with the minor groove mainly through the diazocin bridge. The results suggested the intercalation of one substituent (with additional contacts in the minor groove) as the preferential binding mode for these Tröger bases, while minor groove binding may explain the weaker binding observed for the dextrorotatory isomers.

Highlights

Molecules capable of binding nucleic acids have long been used as antibiotic and antitumoral drugs due to their cytotoxic effects upon cell growth,[1,2,3,4,5] besides being important tools in molecular biology in the form of fluorescent dyes
In order to access the global stability of DNA, we monitored the root mean square deviation (RMSD) and the number of base-pairs conserved through the time of the simulations (Figure 2)
DNA in minor groove complexes seems to endure structural changes that are similar in magnitude to those arising from the relaxation of DNA structure alone, since RMSD average values from SYM-GROOVE and ASYM-GROOVE systems were close to that from DNA-NOGAP (Figure 2B)

Summary

Introduction

Molecules capable of binding nucleic acids have long been used as antibiotic and antitumoral drugs due to their cytotoxic effects upon cell growth,[1,2,3,4,5] besides being important tools in molecular biology in the form of fluorescent dyes. From the results mentioned above rises the question whether there is a common and unique mechanism of binding for Tröger bases - which would result in a new class of DNA binding agents - or if the V-shaped structure works as a versatile scaffold, which can combine, potentiate or even modify the substituent binding profiles These considerations are reinforced by the fact that the levorotatory isomers (right-handed) have been shown to present higher affinity and sequence-selectivity upon binding than the dextrorotatory isomers (left-handed),[14,15,16] suggesting there may exist more than one mechanism of binding, depending on Tröger chirality. We used the docking complexes as starting structures for molecular dynamic simulations, to

Methods

Results

Conclusion