Unraveling the permeation of reactive species across nitrated membranes by computer simulations
Maria C Oliveira1, Maksudbek Yusupov2, Rodrigo M Cordeiro3
1Research Group PLASMANT, Department of Chemistry, University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium; Centro de Ciências Naturais e Humanas, Universidade Federal do ABC, Avenida dos Estados 5001, CEP 09210-580, Santo André, SP, Brazil.
Abstract:
Reactive oxygen and nitrogen species (RONS) are involved in many biochemical processes, including nitro-oxidative stress that causes cancer cell death, observed in cancer therapies such as photodynamic therapy and cold atmospheric plasma. However, their mechanisms of action and selectivity still remain elusive due to the complexity of biological cells. For example, it is not well known how RONS generated by cancer therapies permeate the cell membrane to cause nitro-oxidative damage. There are many studies dedicated to the permeation of RONS across native and oxidized membranes, but not across nitrated membranes, another lipid product also generated during nitro-oxidative stress. Herein, we performed molecular dynamics (MD) simulations to calculate the free energy barrier of RONS permeation across nitrated membranes. Our results show that hydrophilic RONS, such as hydroperoxyl radical (HO2) and peroxynitrous acid (ONOOH), have relatively low barriers compared to hydrogen peroxide (H2O2) and hydroxyl radical (HO), and are more prone to permeate the membrane than for the native or peroxidized membranes, and similar to aldehyde-oxidized membranes. Hydrophobic RONS like molecular oxygen (O2), nitrogen dioxide (NO2) and nitric oxide (NO) even have insignificant barriers for permeation. Compared to native and peroxidized membranes, nitrated membranes are more permeable, suggesting that we must not only consider oxidized membranes during nitro-oxidative stress, but also nitrated membranes, and their role in cancer therapies.
Insights
Nitrated membranes are more permeable to reactive oxygen and nitrogen species (RONS) than native or oxidized membranes. This finding is crucial for understanding RONS mechanisms in cancer therapies and nitro-oxidative stress.
Area of Science:
- Biochemistry
- Molecular Biology
- Computational Chemistry
Background:
- Reactive oxygen and nitrogen species (RONS) are key mediators in nitro-oxidative stress, implicated in cancer cell death during therapies like photodynamic therapy and cold atmospheric plasma.
- The precise mechanisms by which RONS permeate cell membranes and induce damage remain unclear, particularly across nitrated lipid membranes, a product of nitro-oxidative stress.
Purpose of the Study:
- To investigate the free energy barrier for RONS permeation across nitrated lipid membranes using molecular dynamics simulations.
- To compare the permeability of nitrated membranes to RONS with that of native and oxidized membranes.
Main Methods:
- Molecular dynamics (MD) simulations were employed to calculate the free energy barriers associated with RONS permeation.
- Simulations focused on the passage of various hydrophilic and hydrophobic RONS across different membrane types.
Main Results:
- Hydrophilic RONS (HO2, ONOOH) exhibited lower permeation barriers across nitrated membranes compared to H2O2 and HO, showing increased permeability relative to native/peroxidized membranes.
- Hydrophobic RONS (O2, NO2, NO) demonstrated negligible permeation barriers across nitrated membranes.
- Nitrated membranes were found to be significantly more permeable to RONS than native and peroxidized membranes.
Conclusions:
- Nitrated membranes play a critical role in RONS permeation during nitro-oxidative stress and cancer therapies.
- The study highlights the necessity of considering nitrated membranes alongside oxidized membranes when examining RONS interactions in biological systems and therapeutic contexts.
