1 Supplementary Data Structure-based design of selective high-affinity telomeric quadruplex- binding ligands Caterina Maria Lombardo 1 , Iria Sánchez Martínez 1 , Shozeb Haider 1 , Valérie Gabelica 2 , Edwin De Pauw 2 , John E. Moses 3 and Stephen Neidle 1 * 1 CRUK Biomolecular Structure Group, The School of Pharmacy University of London, 29-39 Brunswick Square, London WC1N 1AX, UK E-mail: stephen.neidle@pharmacy.ac.uk ; Fax: (+44) 20-7753-5970; Tel: (+44) 20-7753- 5969; tel: (+44) 20-7753-5969 2 Physical Chemistry and Mass Spectrometry Laboratory, Department of Chemistry, University of Liege, B-4000 Liege, Belgium 3 The School of Chemistry, University of Nottingham, University Park, Nottingham, NG7 2RD, UK Molecular modeling The crystal structure of the parallel-stranded propeller-loop topology (PDB 1KF1) human telomeric G-quadruplex complexed with BRACO-19 wasobtained from the Protein Data Bank and used as a starting point to examine plausible interactions with the ligands. The molecular models for the triazole series of ligands were constructed, minimized and partial charges calculated semi-empirically using the MOPAC program 1 from the Insight suite software (www.accelrys.com). The ligands were minimized and docked using the AFFINITY docking program (www.accelrys.com), employing the grid docking method available with AFFINITY. This approach has been validated in previous studies from this laboratory (see reference list) on the rational design of quadruplex ligands. The automated docking process identifies and ranks positions based on high interaction energies within the binding site. The complexes were then subjected to 1000 steps of molecular mechanics minimization and 200ps of molecular dynamics simulations in explicit solvent at 300K using the DISCOVER3 program in the Insight II suite software. The data was visualized by means of the VMD program. 2 Electrostatic contributions to the overall binding energy were calculated using the APBS software, employing an implicit solvent model. 3 The docked complexes were prepared using the PDB2PQR server (http://agave.wustl.edu/pdb2pqr ). Charges, atom types and radii were assigned to each ligand atom based on the AMBER force field. The complexes were then subjected to APBS electrostatic calculations. A dielectric constant of 2, a solvent dielectric constant of 80 were used, together with grid spacing that were all optimally chosen such that the grid was always finer than 0.5 Å. The remaining parameters were kept at default Supplementary Material (ESI) for Chemical Communications This journal is (c) The Royal Society of Chemistry 2010