HAL Id: hal-02114267
https://hal.archives-ouvertes.fr/hal-02114267
Submitted on 29 Apr 2019
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Insights into DNA lesions formation and structural
outcome by simulation tools
Elise Dumont, Chen-Hui Chan, Emmanuelle Bignon, François Dehez, Antonio
Monari
To cite this version:
Elise Dumont, Chen-Hui Chan, Emmanuelle Bignon, François Dehez, Antonio Monari. Insights into DNA lesions formation and structural outcome by simulation tools. Fifteenth edition of the interna-tional Workshop on Radiation Damage to DNA, May 2018, Aussois, France. �hal-02114267�
Structural insights into complex DNA lesions (and their proteins
…)
ons with
protein
Insights into DNA lesions forma<on and structural outcome
by simula<on tools.
Elise Dumont
1, Chen-Hui Chan
1, Emmanuelle Bignon
1, Francois Dehez
2, Antonio Monari
21Laboratoire de Chimie, Ecole normale supérieure de Lyon and CNRS, 46 allée d'Italie, 69364 Lyon Cedex 07, France. 2Université de Lorraine & CNRS, LPCT, Nancy F-54000 France
Context and our computa<onal tools
Forma<on of intrastrand CLs
Interstrand lesions via C4’-oxidized abasic sites
Modelling can get insights and provide a same-foo<ng comparison: compare reacVvity ? ΔΔG≠ ease of formaVon ? ΔΔGdestab
Molecular dynamics MD (AMBER or NAMD GPU-accelerated) with accurate force field ; DFT calculaVons (eventually coupled to MD) We can extract characterisVc B-helix angles (coll. F. Lankas) and reveal non-covalent interacVons that stabilize damaged duplexes. G-to-T spin density relocaliza<on ΔG‡ = 10±1 kcal/mol
Structural predic<ons and destabiliza<on
free energies
N NH O O N NH N N O O NH2 O H3C HO Postulated, mulV-step mechanism. Why no purines derivaVves ? 5’ 3’ K 3’ 5’ C6 C8 G19 G21 C7 MD show only cytosine leads to a stable interacVon with K Biochemistry 2013 52:8115 5’ 3’ A G A G A G R° A G A G T T C T C T C A T C T C A 5’ 3’DFT-D screening and QM/MM-MD refinement
ΔG‡ -> easy process ! Structure, helical distor<on Classical MD, NCI Relaxation Similarity G[8-5m]T and G[8-5]C Unravelling DNA-photosensiVzer interacVons We generate UV-Vis or CD spectra, invesVgate energy transfer.. J. Phys. Chem. Lei. 2013, 4:4119 Fairly easy reacVon ! Model DFT calculaVons : C ~ A < G Collaborators: F. Lankas (Praha), C. Fonseca-Guerra (Amsterdam) This work was performed within the framework of the LABEX PRIMES (ANR-11-LABEX-0063) of Université de Lyon, within the program "InvesVssements d'Avenir" (ANR-11-IDEX-0007) operated by the French NaVonal Research Agency (ANR) JACS, 2012, 113:2111 Biochemistry 2013 52:425
Mechanis<c insights on radical and ROS reac<vity
6-4PP vs. CPD Dehez et al. NAR 2017 Clustered abasic lesions Bignon et al. NAR 2016 Toward DNA repair Gaiuso et al. JPCL 2016 Damaged N-DNA (ongoing) Several X-ray structures of damaged N-DNA have become available. At the µs range, we probe contrasted mechanical pro- perVes (inward vs. outward). Methodological calibraVon is also needed… Polymorphism of the 6-4PP-containing oligo- nucleoVde at the µs Vme scale Also for Peroxyl-mediated, combinatorial chemistry OBC 2013 11:3038 Singlet oxygen NAR 2016, Chem. Eur. J. 2017 E=0 ΔE=-22.4 ΔE=-108.7 ΔE=-137.9 ΔE=-110.7 ΔE=-58.3 Eact ~ 40 kcal/mol… with three water molecules, not offeredwithin B-DNA
Eact~12
Energy are given in kcal/mol Level of theory LC-BLYP/DZP++
