[Paper Review] Blocking of DNA specific recognition sites by hydrogen peroxide molecules in the process of ion beam therapy of cancer cells

Oleksii Zdorevskyi, D. V. Piatnytskyi+1 more|arXiv (Cornell University)|Nov 27, 2018

Free Radicals and AntioxidantsChemistry17 references3 citations

TL;DR

This study proposes that hydrogen peroxide (H₂O₂), a byproduct of ion beam therapy, can block DNA's specific recognition sites—particularly nucleic bases—by forming more stable complexes than water, thereby inhibiting genetic information transfer in cancer cells. Using atom-atom potential functions and density functional theory (B3LYP), the authors demonstrate that H₂O₂ binds more strongly than H₂O to adenine, thymine, guanine, and cytosine at key sites, especially in major/minor grooves and via complementary hydrogen bonding, suggesting a novel mechanism for cancer cell deactivation.

ABSTRACT

After irradiation of cancer cells in the ion beam therapy method the concentration of hydrogen peroxide in the cell medium grows significantly. But the role of hydrogen peroxide molecules in cancer treatment has not been determined yet. We assume that interaction of peroxide molecules with DNA atomic groups can block the genetic information of the cancer cell and lead to its neutralization. To understand the possibility of DNA deactivation in the cell, in the present study the formation of complexes of hydrogen peroxide molecules with DNA specific recognition sites (nucleic bases) is considered. Using atom-atom potential functions method and quantum-chemical approach, based on density functional theory, the spatial configurations and energy minima for the complexes of peroxide and water molecules with nucleic bases are studied. The most probable positions of hydrogen peroxide molecules interacting with nucleic bases are determined, and the possibility of blocking of genetic information transfer processes is shown. The obtained data allows us to formulate a new mechanism of the ion irradiation action on living cells, that can be useful for cancer treatment.

Motivation & Objective

• To investigate whether hydrogen peroxide (H₂O₂) molecules, produced during ion beam therapy, can bind to DNA nucleic bases and block genetic information transfer.
• To compare the binding affinity of H₂O₂ and H₂O to specific DNA recognition sites (adenine, thymine, guanine, cytosine) under physiological conditions.
• To determine if H₂O₂ forms more stable complexes than water at these sites, potentially disrupting protein-DNA recognition and transcription processes.
• To explore the structural and energetic feasibility of H₂O₂ binding to DNA bases using quantum-chemical and classical potential methods.
• To propose a new mechanism of ion beam therapy action based on molecular blocking of DNA recognition sites by H₂O₂, beyond double-strand breaks.

Proposed method

• Employed atom-atom potential functions (AAPF) to model intermolecular interactions between H₂O₂, H₂O, and DNA bases (A, T, G, C).
• Applied density functional theory (DFT) with the B3LYP functional to calculate electronic structure, interaction energies, and molecular deformations in H₂O₂–DNA complexes.
• Identified stable spatial configurations of H₂O₂ and H₂O complexes with nucleic bases by locating energy minima in potential energy surfaces.
• Calculated interaction energies and deformation energies for both H₂O₂ and H₂O complexes to assess binding strength and molecular flexibility.
• Analyzed binding sites in major and minor grooves of DNA, as well as complementary hydrogen bonding sites, to evaluate functional interference with transcription and protein recognition.
• Validated results across both AAPF and B3LYP methods to ensure consistency and reliability of predicted binding preferences.

Experimental results

Research questions

• RQ1 Can hydrogen peroxide (H₂O₂) form more stable complexes with DNA nucleic bases than water (H₂O) at physiological conditions?
• RQ2 Which specific sites on adenine, thymine, guanine, and cytosine are most favorable for H₂O₂ binding, and how do they compare to H₂O binding?
• RQ3 Does H₂O₂ binding to DNA bases disrupt protein-DNA recognition or transcription processes by blocking key recognition sites?
• RQ4 What is the role of molecular deformation (e.g., dihedral angle changes) in H₂O₂’s ability to form stable complexes with DNA bases?
• RQ5 Can H₂O₂ binding to DNA bases serve as a viable alternative or complementary mechanism to DNA double-strand breaks in ion beam therapy?

Key findings

• H₂O₂ forms more stable complexes than H₂O with all four nucleic bases (adenine, thymine, guanine, cytosine), as confirmed by both AAPF and B3LYP methods.
• For thymine, H₂O₂ binds preferentially at two sites (T-I and T-II) via complementary hydrogen bonds, with significantly higher interaction energy than water.
• In the case of cytosine, H₂O₂ binds at site C-I (more favorable than water) and exclusively at site C-III, while AAPF shows no binding at C-II due to geometric constraints.
• For guanine, H₂O₂ binds at four sites (G-I to G-IV), with the G-I complex showing significant molecular deformation (2.5 kcal/mol) under B3LYP, affecting bond distances.
• At cytosine site C-II, H₂O₂ undergoes a large dihedral angle change (deformation energy 4.2 kcal/mol) to form two hydrogen bonds, enabling stable complex formation.
• The results indicate that H₂O₂ can effectively block DNA recognition sites in both major and minor grooves, potentially disrupting protein-DNA interactions and transcription processes.