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

Rakesh Kumar Mishra1, Lakshmi Maganti2

  • 1School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi, India.

Journal of Biomolecular Structure & Dynamics
|August 6, 2021
PubMed

Insights

Covalently bonded drugs significantly enhance double-stranded DNA (dsDNA) stability against rupture and unzipping forces. This study reveals insights into DNA mechanics crucial for developing new anti-cancer drugs.

Area of Science:

  • Molecular Biology
  • Biophysics
  • Computational Chemistry

Background:

  • DNA denaturation is vital for cellular functions like replication and transcription.
  • Cancerous cell growth presents a major therapeutic challenge.
  • DNA cross-linking agents show potential in killing cancer cells by damaging DNA.

Purpose of the Study:

  • To investigate the impact of rupture and unzipping forces on double-stranded DNA (dsDNA) stability.
  • To analyze these effects in the presence and absence of covalently bonded drugs.
  • To understand the molecular mechanisms underlying drug-induced DNA stabilization.

Main Methods:

  • Steered molecular dynamics (SMD) simulations were employed.
  • Analysis focused on force-induced dsDNA rupture and unzipping.
  • Microscopic examination of hydrogen bond disruption and base-pair stacking overlap variations was performed.

Main Results:

  • dsDNA stability is significantly increased when covalently bonded drugs are present.
  • Rupture events showed symmetry, while unzipping events exhibited asymmetry.
  • Microscopic analysis provided evidence for these mechanical differences.

Conclusions:

  • Covalently bonded drugs enhance dsDNA stability, potentially offering a new therapeutic strategy.
  • The study elucidates the mechanism of force-induced DNA helix opening.
  • Findings may guide the pharmaceutical design of novel anti-cancer drugs targeting DNA.
Keywords:
Molecular dynamicsforce inducedstacking parametersumbrella sampling

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