46
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Understanding DNA under oxidative stress and sensitization: the role of molecular modeling

      review-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          DNA is constantly exposed to damaging threats coming from oxidative stress, i.e., from the presence of free radicals and reactive oxygen species. Sensitization from exogenous and endogenous compounds that strongly enhance the frequency of light-induced lesions also plays an important role. The experimental determination of DNA lesions, though a difficult subject, is somehow well established and allows to elucidate even extremely rare DNA lesions. In parallel, molecular modeling has become fundamental to clearly understand the fine mechanisms related to DNA defects induction. Indeed, it offers an unprecedented possibility to get access to an atomistic or even electronic resolution. Ab initio molecular dynamics may also describe the time-evolution of the molecular system and its reactivity. Yet the modeling of DNA (photo-)reactions does necessitate elaborate multi-scale methodologies to tackle a damage induction reactivity that takes place in a complex environment. The double-stranded DNA environment is first characterized by a very high flexibility, but also a strongly inhomogeneous electrostatic embedding. Additionally, one aims at capturing more subtle effects, such as the sequence selectivity which is of critical important for DNA damage. The structure and dynamics of the DNA/sensitizers complexes, as well as the photo-induced electron- and energy-transfer phenomena taking place upon sensitization, should be carefully modeled. Finally the factors inducing different repair ratios for different lesions should also be rationalized. In this review we will critically analyze the different computational strategies used to model DNA lesions. A clear picture of the complex interplay between reactivity and structural factors will be sketched. The use of proper multi-scale modeling leads to the in-depth comprehension of DNA lesions mechanisms and also to the rational design of new chemo-therapeutic agents.

          Related collections

          Most cited references109

          • Record: found
          • Abstract: found
          • Article: not found

          QM/MM methods for biomolecular systems.

          Combined quantum-mechanics/molecular-mechanics (QM/MM) approaches have become the method of choice for modeling reactions in biomolecular systems. Quantum-mechanical (QM) methods are required for describing chemical reactions and other electronic processes, such as charge transfer or electronic excitation. However, QM methods are restricted to systems of up to a few hundred atoms. However, the size and conformational complexity of biopolymers calls for methods capable of treating up to several 100,000 atoms and allowing for simulations over time scales of tens of nanoseconds. This is achieved by highly efficient, force-field-based molecular mechanics (MM) methods. Thus to model large biomolecules the logical approach is to combine the two techniques and to use a QM method for the chemically active region (e.g., substrates and co-factors in an enzymatic reaction) and an MM treatment for the surroundings (e.g., protein and solvent). The resulting schemes are commonly referred to as combined or hybrid QM/MM methods. They enable the modeling of reactive biomolecular systems at a reasonable computational effort while providing the necessary accuracy.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Superoxide radical and superoxide dismutases.

            O2- oxidizes the [4Fe-4S] clusters of dehydratases, such as aconitase, causing-inactivation and release of Fe(II), which may then reduce H2O2 to OH- +OH.. SODs inhibit such HO. production by scavengingO2-, but Cu, ZnSODs, by virtue of a nonspecific peroxidase activity, may peroxidize spin trapping agents and thus give the appearance of catalyzing OH. production from H2O2. There is a glycosylated, tetrameric Cu, ZnSOD in the extracellular space that binds to acidic glycosamino-glycans. It minimizes the reaction of O2- with NO. E. coli, and other gram negative microorganisms, contain a periplasmic Cu, ZnSOD that may serve to protect against extracellular O2-. Mn(III) complexes of multidentate macrocyclic nitrogenous ligands catalyze the dismutation of O2- and are being explored as potential pharmaceutical agents. SOD-null mutants have been prepared to reveal the biological effects of O2-. SodA, sodB E. coli exhibit dioxygen-dependent auxotrophies and enhanced mutagenesis, reflecting O2(-)-sensitive biosynthetic pathways and DNA damage. Yeast, lacking either Cu, ZnSOD or MnSOD, are oxygen intolerant, and the double mutant was hypermutable and defective in sporulation and exhibited requirements for methionine and lysine. A Cu, ZnSOD-null Drosophila exhibited a shortened lifespan.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Oxidative stress and oxidative damage in carcinogenesis.

              Carcinogenesis is a multistep process involving mutation and the subsequent selective clonal expansion of the mutated cell. Chemical and physical agents including those that induce reative oxygen species can induce and/or modulate this multistep process. Several modes of action by which carcinogens induce cancer have been identified, including through production of reactive oxygen species (ROS). Oxidative damage to cellular macromolecules can arise through overproduction of ROS and faulty antioxidant and/or DNA repair mechanisms. In addition, ROS can stimulate signal transduction pathways and lead to activation of key transcription factors such as Nrf2 and NF-kappaB. The resultant altered gene expression patterns evoked by ROS contribute to the carcinogenesis process. Recent evidence demonstrates an association between a number of single nucleotide polymorphisms (SNPs) in oxidative DNA repair genes and antioxidant genes with human cancer susceptibility. These aspects of ROS biology will be discussed in the context of their relationship to carcinogenesis.
                Bookmark

                Author and article information

                Contributors
                Journal
                Front Chem
                Front Chem
                Front. Chem.
                Frontiers in Chemistry
                Frontiers Media S.A.
                2296-2646
                14 July 2015
                2015
                : 3
                : 43
                Affiliations
                [1] 1Laboratoire de Chimie, UMR 5182 Centre National de la Recherche Scientifique, École Normale Supérieure de Lyon Lyon, France
                [2] 2Université de Lorraine - Nancy, Theory-Modeling-Simulation, Structure et Réactivité des Systèmes Moléculaires Complexes (SRSMC) Vandoeuvre-les-Nancy, France
                [3] 3Centre National de la Recherche Scientifique, Theory-Modeling-Simulation, Structure et Réactivité des Systèmes Moléculaires Complexes (SRSMC) Vandoeuvre-les-Nancy, France
                Author notes

                Edited by: John D. Wade, Florey Institute of Neuroscience and Mental Health, Australia

                Reviewed by: Robert Vianello, Rudjer Boskovic Institute, Croatia; Giampaolo Barone, University of Palermo, Italy

                *Correspondence: Elise Dumont, Laboratoire de Chimie, UMR 5182 Centre National de la Recherche Scientifique, École Normale Supérieure de Lyon, 46, Allée d'Italie, 69364 Lyon 07, France elise.dumont@ 123456ens-lyon.fr ;
                Antonio Monari, Faculté de Sciences et Techniques, Boulevard des Aiguillettes, Vandoeuvre-les-Nancy, 54506 Nancy, France antonio.monari@ 123456univ-lorraine.fr

                This article was submitted to Chemical Biology, a section of the journal Frontiers in Chemistry

                Article
                10.3389/fchem.2015.00043
                4500984
                26236706
                9004b5c6-94e9-4316-ab2b-7a980a1eb8ec
                Copyright © 2015 Dumont and Monari.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution and reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 27 March 2015
                : 29 June 2015
                Page count
                Figures: 3, Tables: 0, Equations: 0, References: 130, Pages: 15, Words: 13845
                Categories
                Chemistry
                Review

                dna,photosensitization,photodynamic therapy,photochemistry,molecular modeling,energy/electron transfer

                Comments

                Comment on this article