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Probing the reactivity of singlet oxygen with purines

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      Abstract

      The reaction of singlet molecular oxygen with purine DNA bases is investigated by computational means. We support the formation of a transient endoperoxide for guanine and by classical molecular dynamics simulations we demonstrate that the formation of this adduct does not affect the B-helicity. We thus identify the guanine endoperoxide as a key intermediate, confirming a low-temperature nuclear magnetic resonance proof of its existence, and we delineate its degradation pathway, tracing back the preferential formation of 8-oxoguanine versus spiro-derivates in B-DNA. Finally, the latter oxidized 8-oxodGuo product exhibits an almost barrierless reaction profile, and hence is found, coherently with experience, to be much more reactive than guanine itself. On the contrary, in agreement with experimental observations, singlet-oxygen reactivity onto adenine is kinetically blocked by a higher energy transition state.

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      Development and testing of a general amber force field.

      We describe here a general Amber force field (GAFF) for organic molecules. GAFF is designed to be compatible with existing Amber force fields for proteins and nucleic acids, and has parameters for most organic and pharmaceutical molecules that are composed of H, C, N, O, S, P, and halogens. It uses a simple functional form and a limited number of atom types, but incorporates both empirical and heuristic models to estimate force constants and partial atomic charges. The performance of GAFF in test cases is encouraging. In test I, 74 crystallographic structures were compared to GAFF minimized structures, with a root-mean-square displacement of 0.26 A, which is comparable to that of the Tripos 5.2 force field (0.25 A) and better than those of MMFF 94 and CHARMm (0.47 and 0.44 A, respectively). In test II, gas phase minimizations were performed on 22 nucleic acid base pairs, and the minimized structures and intermolecular energies were compared to MP2/6-31G* results. The RMS of displacements and relative energies were 0.25 A and 1.2 kcal/mol, respectively. These data are comparable to results from Parm99/RESP (0.16 A and 1.18 kcal/mol, respectively), which were parameterized to these base pairs. Test III looked at the relative energies of 71 conformational pairs that were used in development of the Parm99 force field. The RMS error in relative energies (compared to experiment) is about 0.5 kcal/mol. GAFF can be applied to wide range of molecules in an automatic fashion, making it suitable for rational drug design and database searching. Copyright 2004 Wiley Periodicals, Inc.
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        Quantum mechanical continuum solvation models.

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          Refinement of the AMBER force field for nucleic acids: improving the description of alpha/gamma conformers.

          We present here the parmbsc0 force field, a refinement of the AMBER parm99 force field, where emphasis has been made on the correct representation of the alpha/gamma concerted rotation in nucleic acids (NAs). The modified force field corrects overpopulations of the alpha/gamma = (g+,t) backbone that were seen in long (more than 10 ns) simulations with previous AMBER parameter sets (parm94-99). The force field has been derived by fitting to high-level quantum mechanical data and verified by comparison with very high-level quantum mechanical calculations and by a very extensive comparison between simulations and experimental data. The set of validation simulations includes two of the longest trajectories published to date for the DNA duplex (200 ns each) and the largest variety of NA structures studied to date (15 different NA families and 97 individual structures). The total simulation time used to validate the force field includes near 1 mus of state-of-the-art molecular dynamics simulations in aqueous solution.
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            Author and article information

            Affiliations
            [1 ]Laboratoire de Chimie, UMR 5182, Ecole Normale Supérieure de Lyon, Lyon France
            [2 ]Institut des Sciences Analytiques, Université de Lyon 1 and CNRS, Villeurbanne, France
            [3 ]iRTSV/CBM/MCT, CEA Grenoble, France
            [4 ]Theory-Modeling-Simulation, SRSMC, Université de Lorraine Nancy, Vandoeuvre-lès-Nancy, France
            [5 ]CNRS, Theory-Modeling-Simulation, SRSMC, Vandoeuvre-lès-Nancy, France
            [6 ]INAC-SCIB, Université Grenoble Alpes, F-38000 Grenoble, France
            [7 ]CEA, INAC-SCIB-LAN, F-38000 Grenoble, France
            Author notes
            [* ]To whom correspondence should be addressed. Tel: +33 4 72 72 88 46; Email: elise.dumont@ 123456ens-lyon.fr
            Correspondence may also be addressed to Jean-Luc Ravanat. Tel: +33 38 78 47 97; Email: jean-luc.ravanat@ 123456cea.fr
            Journal
            Nucleic Acids Res
            Nucleic Acids Res
            nar
            nar
            Nucleic Acids Research
            Oxford University Press
            0305-1048
            1362-4962
            08 January 2016
            09 December 2015
            09 December 2015
            : 44
            : 1
            : 56-62
            26656495
            4705671
            10.1093/nar/gkv1364
            © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

            This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@ 123456oup.com

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            Pages: 7
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            Categories
            Chemical Biology and Nucleic Acid Chemistry
            Custom metadata
            08 January 2016

            Genetics

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