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Title: Molecular mechanism and binding free energy of doxorubicin intercalation in DNA

Abstract

The intercalation process of binding doxorubicin (DOX) in DNA is studied by extensive MD simulations. Many molecular factors that control the binding affinity of DOX to DNA to form a stable complex are inspected and quantified by employing continuum solvation models for estimating the binding free energy. The modified MM-PB(GB)SA methodology provides a complete energetic profile of Δ G ele, Δ G vDW, Δ G polar, Δ G non-polar, TΔ S total, Δ G deform, Δ G con, and Δ G ion. To identify the sequence specificity of DOX, two different DNA sequences, d(CGATCG) or DNA1 and d(CGTACG) or DNA2, with one molecule (1 : 1 complex) or two molecule (2 : 1 complex) configurations of DOX were selected in this study. Our results show that the DNA deformation energy (Δ G deform), the energy cost from translational and rotational entropic contributions ( TΔ S tran+rot), the total electrostatic interactions (Δ G polar-PB/GB + Δ G ele) of incorporation, the intramolecular electrostatic interactions (Δ G ele) and electrostatic polar solvation interactions (Δ G polar-PB/GB) are all unfavorable to the binding of DOX to DNA. However, they are overcome by at least five favorable interactions: the van der Waals interactions (Δmore » G vDW), the non-polar solvation interaction (Δ G non-polar), the vibrational entropic contribution ( TΔ S vib), and the standard concentration dependent free energies of DOX (Δ G con) and the ionic solution (Δ G ion). Specifically, the van der Waals interaction appears to be the major driving force to form a stable DOX–DNA complex. We also predict that DOX has stronger binding to DNA1 than DNA2. The DNA deformation penalty and entropy cost in the 2 : 1 complex are less than those in the 1 : 1 complex, thus they indicate that the 2 : 1 complex is more stable than the 1 : 1 complex. Here, we have calculated the total binding free energy (BFE) (Δ G t-sim) using both MM-PBSA and MM-GBSA methods, which suggests a more stable DOX–DNA complex at lower ionic concentration. The calculated BFE from the modified MM-GBSA method for DOX–DNA1 and DOX–DNA2 in the 1 : 1 complex is –9.1 and –5.1 kcal mol –1 respectively. The same quantities from the modified MM-PBSA method are –12.74 and –8.35 kcal mol –1 respectively. The value of the total BFE Δ G t-sim in the 1 : 1 complex is in reasonable agreement with the experimental value of –7.7 ± 0.3 kcal mol –1.« less

Authors:
 [1];  [2];  [3];  [4]; ORCiD logo [2]
  1. Univ. of Missouri-Kansas City, Kansas City, MO (United States); Univ. of Technology, Baghdad (Iraq)
  2. Univ. of Missouri-Kansas City, Kansas City, MO (United States)
  3. Univ. of Chinese Academy of Sciences, Beijing (China); Chinese Academy of Sciences, Beijing (China)
  4. Univ. of California-San Diego, La Jolla, CA (United States)
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). National Energy Research Scientific Computing Center (NERSC); Univ. of California, San Diego, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1543801
Grant/Contract Number:  
AC03-76SF00098
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Physical Chemistry Chemical Physics. PCCP (Print)
Additional Journal Information:
Journal Volume: 21; Journal Issue: 7; Journal ID: ISSN 1463-9076
Publisher:
Royal Society of Chemistry
Country of Publication:
United States
Language:
English
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; Chemistry; Physics

Citation Formats

Jawad, Bahaa, Poudel, Lokendra, Podgornik, Rudolf, Steinmetz, Nicole F., and Ching, Wai -Yim. Molecular mechanism and binding free energy of doxorubicin intercalation in DNA. United States: N. p., 2019. Web. doi:10.1039/c8cp06776g.
Jawad, Bahaa, Poudel, Lokendra, Podgornik, Rudolf, Steinmetz, Nicole F., & Ching, Wai -Yim. Molecular mechanism and binding free energy of doxorubicin intercalation in DNA. United States. https://doi.org/10.1039/c8cp06776g
Jawad, Bahaa, Poudel, Lokendra, Podgornik, Rudolf, Steinmetz, Nicole F., and Ching, Wai -Yim. Fri . "Molecular mechanism and binding free energy of doxorubicin intercalation in DNA". United States. https://doi.org/10.1039/c8cp06776g. https://www.osti.gov/servlets/purl/1543801.
@article{osti_1543801,
title = {Molecular mechanism and binding free energy of doxorubicin intercalation in DNA},
author = {Jawad, Bahaa and Poudel, Lokendra and Podgornik, Rudolf and Steinmetz, Nicole F. and Ching, Wai -Yim},
abstractNote = {The intercalation process of binding doxorubicin (DOX) in DNA is studied by extensive MD simulations. Many molecular factors that control the binding affinity of DOX to DNA to form a stable complex are inspected and quantified by employing continuum solvation models for estimating the binding free energy. The modified MM-PB(GB)SA methodology provides a complete energetic profile of ΔGele, ΔGvDW, ΔGpolar, ΔGnon-polar, TΔStotal, ΔGdeform, ΔGcon, and ΔGion. To identify the sequence specificity of DOX, two different DNA sequences, d(CGATCG) or DNA1 and d(CGTACG) or DNA2, with one molecule (1 : 1 complex) or two molecule (2 : 1 complex) configurations of DOX were selected in this study. Our results show that the DNA deformation energy (ΔGdeform), the energy cost from translational and rotational entropic contributions (TΔStran+rot), the total electrostatic interactions (ΔGpolar-PB/GB + ΔGele) of incorporation, the intramolecular electrostatic interactions (ΔGele) and electrostatic polar solvation interactions (ΔGpolar-PB/GB) are all unfavorable to the binding of DOX to DNA. However, they are overcome by at least five favorable interactions: the van der Waals interactions (ΔGvDW), the non-polar solvation interaction (ΔGnon-polar), the vibrational entropic contribution (TΔSvib), and the standard concentration dependent free energies of DOX (ΔGcon) and the ionic solution (ΔGion). Specifically, the van der Waals interaction appears to be the major driving force to form a stable DOX–DNA complex. We also predict that DOX has stronger binding to DNA1 than DNA2. The DNA deformation penalty and entropy cost in the 2 : 1 complex are less than those in the 1 : 1 complex, thus they indicate that the 2 : 1 complex is more stable than the 1 : 1 complex. Here, we have calculated the total binding free energy (BFE) (ΔGt-sim) using both MM-PBSA and MM-GBSA methods, which suggests a more stable DOX–DNA complex at lower ionic concentration. The calculated BFE from the modified MM-GBSA method for DOX–DNA1 and DOX–DNA2 in the 1 : 1 complex is –9.1 and –5.1 kcal mol–1 respectively. The same quantities from the modified MM-PBSA method are –12.74 and –8.35 kcal mol–1 respectively. The value of the total BFE ΔGt-sim in the 1 : 1 complex is in reasonable agreement with the experimental value of –7.7 ± 0.3 kcal mol–1.},
doi = {10.1039/c8cp06776g},
url = {https://www.osti.gov/biblio/1543801}, journal = {Physical Chemistry Chemical Physics. PCCP (Print)},
issn = {1463-9076},
number = 7,
volume = 21,
place = {United States},
year = {2019},
month = {1}
}

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