Antitumor drugs effect on the stability of double-stranded DNA: steered molecular dynamics analysis

Abstract

Denaturation of the DNA double helix inside the cell is essential for cellular processes such as replication and transcription for the growth of the cells. However, the growth of unwanted cells, which are responsible for cancerous kind of disease, is one of the biggest challenges of modern therapeutics. DNA cross-linking agents may kill cancer cells by damaging their DNA and stopping them from dividing. In the present study, we have carried out steered molecular dynamics simulations to study the effects of rupture and unzipping forces on the stability of dsDNA in the absence and presence of covalently bonded drugs. We have found that the stability of dsDNA increases strongly in the presence of covalently bonded drugs. The microscopic study of disruption of hydrogen-bonds associated with base-pairs of the dsDNA and the study of the variation of stacking overlap parameters gives evidence of symmetry during the rupture and asymmetry in the unzip event. The significance of the mechanism of force-induced melting study of the dsDNA in the absence and presence of antitumor drugs might have a biological relevance as it provides a pathway to open the double helix in a specific position and may help for the pharmaceutical design of drugs.

Communicated by Ramaswamy H. Sarma

Keywords:

• Molecular dynamics
• force induced
• stacking parameters
• umbrella sampling

Acknowledgments

We thank Prof. Dhananjay Bhattacharyya of Saha Institute of Nuclear Physics, Dr. Sheshnath, and Dr. Garima Mishra for stimulating discussions on the subject. We also thank the cluster of CAPP-II projects of DAE for providing computational support for simulation. We gratefully acknowledge the DST and SERB India, with grant number PDF/2015/000308. RKM also thank to UGC for D. S. Kothari fellowship with the award number F4-2/2006(BSR)/PHY/18-19/0060.

Additional information

Funding

We thank Prof. Dhananjay Bhattacharyya of Saha Institute of Nuclear Physics, Dr. Sheshnath, and Dr. Garima Mishra for stimulating discussions on the subject. We also thank the cluster of CAPP-II projects of DAE for providing computational support for simulation. We gratefully acknowledge the DST and SERB India, with grant number PDF/2015/000308. RKM also thank to UGC for D. S. Kothari fellowship with the award number F4-2/2006(BSR)/PHY/18-19/0060.