Force-induced rupture of double-stranded DNA in the absence and presence of covalently bonded anti-tumor drugs: Insights from molecular dynamics simulations

Abstract

DNA intra-strand cross-link (ICL) agents are widely used in the treatment of cancer. ICLs are thought to form a link between the same strand (intra-strand) or complimentary strand (inter-strand) and thereby increase the stability of DNA, which forbids the processes like replication and transcription. As a result, cell death occurs. In this work, we have studied the enhanced stability of a double stranded DNA in the presence of ICLs and compared our findings with the results obtained in the absence of these links. Using atomistic simulations with explicit solvent, a force is applied along and perpendicular to the direction of the helix and we measured the rupture force and the unzipping force of DNA-ICL complexes. Our results show that the rupture and the unzipping forces increase significantly in the presence of these links. The ICLs bind to the minor groove of DNA, which enhance the DNA stabilisation. Such information may be used to design alternative drugs that can stall replication and transcription that are critical to a growing number of anticancer drug discovery efforts.

Single-photon ionization induced C–C or C–N bond formation in pyrrole clusters

“…Radiation-induced generation of photodimers of nitrogen heterocyclic compounds (NHCs) is one of the important molecular mechanisms of DNA damage. [1][2][3][4] It causes a severe threat to human health owing to disparate cellular responses elicited following DNA damage and ultimately causing various tumors. 5,6 The inter-/intra-molecular interactions of NHCs regulate many chemical and biological processes.…”

Understanding enhanced mechanical stability of DNA in the presence of intercalated anticancer drug: Implications for DNA associated processes

“…13 These experimental results have also not been studied by simulations, except in references. 22,23,27 In particular, little seems to be known about the details of the effects of small-molecule binding on the functions of dsDNA, such as its dissociation mechanics.…”