Electronic Supplementary Material (ESI) for Physical Chemistry Chemical Physics.
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Supporting Information for:
Free energy profiles for two ubiquitous damaging
agents: methylation and hydroxylation of
guanine in B-DNA
Raymond Grüber,† Juan Aranda,‡ Ayad Bellili,† Iñaki Tuñón,‡ and Elise
Dumont∗,†
†Univ Lyon, Ens de Lyon, CNRS, Universit Lyon 1, Laboratoire de Chimie UMR 5182,
F-69342, Lyon, France
‡Departament Quı́mica Fı́sica Universidad de València 46100 Burjassot, Spain
E-mail: [email protected]
Phone: +33 (0)4 72 72 88 46. Fax: +33 (0)4 72 72 88 60
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Classical Molecular dynamics setup
Setup for the NNMe+ . . .duplex system
All preliminary classical molecular dynamics simulations were performed using the Amber12
suite of programs, 1 using the parmbsc0 and Generalized Amber Force Field (GAFF 2 ) force
fields. The self-complementary d(AGAGACGAGAGA) dodecameric sequence was generated
using the nab module of Amber. The methyldiazonium NNMe+ was placed near the guanine
G7, either towards O6 or N7 at a distance of 2 Å between the two atoms that become
covalently tethered. 21 potassium counterions (Dang parameters) were added to the system
in order to neutralize the negatively charged atomic groups of the macromolecule. The
system was placed in a parallelepipedic TIP3P 3 water box with a 10 Å buffer. A 9 Å cutoff
was imposed for electrostatic potential in order to avoid interaction between DNA helix
images due to the periodic boundary conditions.
A representative snapshot was extracted based on a minimal RMSD by cluster analysis. The
two corresponding transition state structures was optimized for the QM/MM system using
the Baker’s algorithm within fdynamo.
Setup for the HO•+ . . .duplex system
Since it is impossible to define a force-field description for the radical hydroxyle interacting
with B-DNA, we generated a ”near-reactant” structure from a previous study where the
singlet oxygen was attacking a guanine embedded in ds-DNA. 4 One of the oxygen atoms (the
one opposite to the DNA strand) was manually replaced by an hydrogen (the interatomic
distance was shortened to a distance of 1.05 Å). This provides a starting point for the
optimization of the TS structure in the B-DNA environment.
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Benchmark of density functionals for the hydroxyle addition
Ten density functionals were tested: but the reactant structure, the guanine+hydroxyle radical system is difficult to benchmark as its geometry is poorly representative and comparable
to the one in B-DNA. All the optimized structures with dispersion-corrected DFT (Grimme’s
D3BJ ? ) predict a stacking of the hydroxyle nearly parralel to the C4=C5 ethylenic bond, at
a distance of 3.4 Å characteristic of dispersion. This induces a stabilization of the reactant
compared to its geometry within B-DNA, and consequently barrierless reaction profiles.
Figure S1: Representative structure of G+HO• reactants optimized with water as a continuum
solvent (PCM).
Given the low barriers towards hydroxylation to guanine, the not so realistic stationary
points jeopardize the relevance of the static reference. For instance, with the GGA BLYP
functional, the transition energy is very close to 0 kcal/mol. This leads us to compare the
performance of three density functionals along the QM/MM-MD free energy profile.
Along this benchmark, one notes that values of exothermicities varies with the density functional, notably with the percentage of exact exchange.
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Table S1: Activation energies ∆E † calculated in kcal/mol with ten density functionals for the
attack of NNCH3 + onto guanine: the 6-31G(d) basis set is used throughout. Characteristic
distances are given in Å.
N7
†
BLYP-D3BJ
BP86-D3BJ
TPSSTPSS
M06L
B3LYP-D3BJ
PBE0
M06
M06-2X
LC-BLYP-D3BJ
B2PLYP
MP2/cc-pVTZ
∆E
4.6
6.1
3.9
7.2
4.6
6.6
5.3
5.4
6.7
3.5
5.1
O6
†
d
2.40
2.32
2.35
2.31
2.36
2.28
2.38
2.28
2.28
2.35
2.30
†
∆E
5.7
8.1
7.3
8.5
5.9
8.4
6.8
7.3
8.1
4.6
6.4
d†
2.29
2.20
2.23
2.21
2.24
2.16
2.21
2.16
2.14
2.24
2.18
References
(1) Case, D. et al. (2012), AMBER 12, University of California, San Francisco.
(2) Wang, J.; Wolf, R. M.; Caldwell, J. W.; Kollman, P. A.; Case, D. A. Development and
testing of a general amber force field. J. Comput. Chem. 2004, 25, 1157–1174.
(3) Jorgensen, W. L.; Chandrasekhar, J.; Madura, J. D.; Impey, R. W.; Klein, M. L. Comparison of Simple Potential Functions for Simulating Liquid Water. J. Chem. Phys. 1983,
79, 926–935.
(4) Dumont, E.; Grber, R.; Bignon, E.; Morell, C.; Aranda, J.; Ravanat, J.-L.; Tun, I.
Singlet Oxygen Attack on Guanine: Reactivity and Structural Signature within the
B-DNA Helix. Chemistry A European Journal 2016, 22, 12358–12362.
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