for the central scaffold were derived by fitting the HF/6-31G*
electrostatic potential obtained with the GAMESS ab initio
software49 to the atomic centres with the RESP program.50 Atomic
parameters for the peptide side chains were taken directly from
the Amber force field,51 as implemented within Insight II. The
protonation state of the amino acid side chains was determined
based on an assumed physiological pH of 7.0. The N10 position
of the acridine was also protonated with a +1 charge based on
its role as a hydrogen bond donor in a quadruplex-ligand crystal
structure (1L1H).52
5 T. Simonsson, P. Pecinka and M. Kubista, Nucleic Acids Res., 1998, 26,
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Todd, S. Ladame, S. Balasubramanian and S. Neidle, J. Am. Chem.
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7 H. Fernando, A. P. Reszka, J. Huppert, S. Ladame, S. Rankin, A. R.
Venkitaraman, S. Neidle and S. Balasubramanian, Biochemistry, 2006,
45, 7854–7860.
8 S. Kumari, A. Bugaut, J. L. Huppert and S. Balasubramanian, Nature
Chem. Biol., 2007, 3, 218–221.
9 S. Yu, J. L. Huppert, and S. Balasubramanian, unpublished results. See
Supplementary Information for details.
Docking was performed with the Affinity Docking module of
Insight II using a previously-described protocol.36 In this way,
a multi-phase docking protocol was used. First the ligand was
manually displaced along the binding host while interactively
calculating their interaction energy. Once a favourable initial
relative conformation was found a binding pocket which included
10 S. Cogoi, F. Quadrifoglio and L. E. Xodo, Biochemistry, 2004, 43,
2512–2523.
11 S. Cogoi and L. E. Xodo, Nucleic Acids Res., 2006, 34, 2536–2549; S.
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Hurley, J. Am. Chem. Soc., 2007, 129, 10220–10228.
14 D. Sun, K. Guo, J. J. Rusche and L. H. Hurley, Nucleic Acids Res., 2005,
33, 6070–6080; D. Sun, W.-J. Liu, K. Guo, J. J. Rusche, S. Ebbinghaus,
V. Gokhale and L. H. Hurley, Mol. Cancer Ther., 2008, 7, 880–889; K.
Guo, V. Gokhale, L. H. Hurley and D. Sun, Nucleic Acids Res., 2008,
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15 R. De Armond, S. Wood, D. Sun, L. H. Hurley and S. W. Ebbinghaus,
Biochemistry, 2005, 44, 16341–16350.
16 J. Dai, D. Chen, R. A. Jones, L. H. Hurley and D. Yang, Nucleic Acids
Res., 2006, 34, 5133–5144; T. S. Dexheimer, D. Sun and L. H. Hurley,
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17 Y. Qin, E. M. Rezler, V. Gokhale, D. Sun and L. H. Hurley, Nucleic
Acids Res., 2007, 35, 7698–7713.
18 S. L. Palumbo, R. M. Memmott, D. J. Uribe, Y. Krotova-Khan, L. H.
Hurley and S. W. Ebbinghaus, Nucleic Acids Res., 2008, 36, 1755–
1769.
˚
hydrogen atoms 5 A from the ligand was defined, and then
the ligand was randomly orientated with respect to the binding
host 200 times. Van der Waals radii were set to 10% of the full
value, charges were not considered and non-bonded cut-offs were
˚
set to 8 A. The system was minimized for 300 steps using the
conjugate gradient method. The maximum allowable change for
succeeding structures was set to 10000 kcal mol-1 and the energy
range was set to 40 kcal mol-1. The 75 lowest-energy structures
were used for the second phase of the modelling. The second
phase of the docking protocol consisted of a simulated annealing
procedure in which the van der Waals radii were adjusted to
their full values, charges were included with a distance-dependent
˚
dielectric of 4*rij and the non-bonded cut-off was set to 18 A.
Each of the 75 lowest-energy structures was again minimized for
300 steps of conjugate-gradient minimization, and then molecular
dynamics calculations were performed, starting at a temperature
of 500 K and cooling the system to 300 K over 10 ps. The
resulting structures were minimized for 1000 steps of conjugate
gradients and the 25 structures with lowest total energy were used
for further evaluation. These 25 filtered structures were further
refined in order to perform an optimal conformational sampling of
the peptide side-chains while maintaining the ligand orientation.
Hence, the structures were subjected to another run of simulated
annealing in which the binding pocket was extended to contain all
19 A. Siddiqui-Jain, C. L. Grand, D. J. Bearss and L. H. Hurley, Proc.
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20 Y. Mikami-Terao, M. Akiyama, Y. Yuza, T. Yanagisawa, O. Yamada
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25 T. Lemarteleur, D. Gomez, R. Paterski, E. Mandine, P. Maillet and J.-F.
Riou, Biochem. Biophys. Res. Commun., 2004, 323, 802–808.
26 Z. A. E. Waller, P. S. Shirude, R. Rodriguez and S. Balasubramanian,
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27 M. Tera, H. Ishizuka, M. Takagi, M. Suganuma, K. Shin-ya and K.
Nagasawa, Angew. Chem. Int. Ed., 2008, 47, 5557–5560.
28 H. Han, D. R. Langley, A. Rangan and L. H. Hurley, J. Am. Chem.
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2944–2959; D. P. N. Gonc¸alves, R. Rodriguez, S. Balasubramanian and
J. K. M. Sanders, Chem. Commun., 2006, 4685–4687; W.-J. Zhang, T.-
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Wong and L.-Q. Gu, Bioorg. Med. Chem., 2007, 15, 5493–5501; B. Fu,
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˚
atoms 5 A from the ligand while the bases of the G-quartet were
tethered to their original position. The system was cooled down
over 10 ps from 500 K to 300 K, and the resulting structures were
subjected to a 1000 steps of conjugate gradient minimization.
Acknowledgements
We thank Cancer Research UK for programme funding (to SB
and to SN).
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