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Structural Dynamics of Acetylcholinesterase and Its Implications in Reactivators Design Gianluca Santoni

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Structural Dynamics of Acetylcholinesterase and Its Implications in Reactivators Design Gianluca Santoni Structural dynamics of acetylcholinesterase and its implications in reactivators design Gianluca Santoni To cite this version: Gianluca Santoni. Structural dynamics of acetylcholinesterase and its implications in reactivators design. Biomolecules [q-bio.BM]. Université Grenoble Alpes, 2015. English. NNT : 2015GREAY019. tel-01212481 HAL Id: tel-01212481 https://tel.archives-ouvertes.fr/tel-01212481 Submitted on 6 Oct 2015 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. THÈSE Pour obtenir le grade de DOCTEUR DE L’UNIVERSITÉ DE GRENOBLE Spécialité : Physique pour les sciences du vivant Arrêté ministériel : 7 Aout 2006 Présentée par Gianluca SANTONI Thèse dirigée par Martin WEIK et codirigée par Florian NACHON préparée au sein de l’Institut de Biologie Structurale de Grenoble et de l’école doctorale de physique Structural dynamics of acetyl- cholinesterase and its implications in reactivator design Thèse soutenue publiquement le 30/01/2015, devant le jury composé de : Dr. Yves Bourne Directeur de recherche CNRS, AFMB Marseille, Rapporteur Dr. Etienne Derat Maitre de conference, Université Pierre et Marie Curie, Paris, Rapporteur Prof. Pierre-Yves Renard Professeur, Université de Normandie, Rouen, Examinateur Prof. Israel Silman Professeur, Weizmann Institute of Science,Rehovot, Examinateur Dr. Yvain Nicolet Chargé de recherche CNRS, IBS, Grenoble, Examinateur Dr. Jacques-Philippe Colletier Chargé de recherche CNRS, IBS, Grenoble, Examinateur Dr. Martin Weik Directeur de recherche CEA, IBS, Grenoble, Directeur de thèse Dr. Florian Nachon IDEF, IRBA, Bretigny sur Orge, Co-Directeur de thèse THÈSE Pour obtenir le grade de DOCTEUR DE L’UNIVERSITÉ DE GRENOBLE Spécialité : Physique pour les sciences du vivant Arrêté ministériel : 7 Aout 2006 Présentée par Gianluca SANTONI Thèse dirigée par Martin WEIK et codirigée par Florian NACHON préparée au sein institut de biologie structurale de Grenoble et de l’école doctorale de physique Dynamique structurale de l’acetylcholinesterase et ses im- plications dans la conception de reactivateurs. Thèse soutenue publiquement le 30/01/2015, devant le jury composé de : Dr. Yves Bourne Directeur de recherche CNRS, AFMB Marseille, Rapporteur Dr. Etienne Derat Maitre de conference, Université Pierre et Marie Curie, Paris, Rapporteur Prof. Pierre-Yves Renard Professeur, Université de Normandie, Rouen, Examinateur Prof. Israel Silman Professeur, Weizmann institute,Rehovot, Examinateur Dr. Yvain Nicolet Chargé de recherche CNRS, IBS, Grenoble, Examinateur Dr. Jacques-Philippe Colletier Chargé de recherche CNRS, IBS, Grenoble, Examinateur Dr. Martin Weik Directeur de recherche CEA, IBS, Grenoble, Directeur de thèse Dr. Florian Nachon IDEF, IRBA, Bretigny sur Orge, Co-Directeur de thèse Contents Preface 1 1 Acetylcholinesterase 3 1.1 Biological function . 3 1.2 Structure and dynamics of AChE . 4 1.2.1 Three dimensional structure of AChE . 4 1.2.2 Structural dynamics involved in substrate traffic and ligand binding .............................. 7 1.2.3 Human AChE crystals . 8 1.3 Organophosphates and their inhibition of AChE . 9 1.3.1 Inhibition mechanism . 10 1.3.2 Three dimensional structures of OP-inhibited AChE . 11 1.3.3 Treatment of OP intoxication . 12 2 Drug design and protein flexibility 17 2.1 Structure based drug design (SBDD) . 18 2.1.1 Definition of structure based drug design . 18 2.1.2 The search for new ligands . 18 2.2 Protein structural dynamics . 19 2.2.1 The conformational landscape of proteins . 19 2.2.2 Techniques to characterize protein structural dynamics . 21 2.3 Including dynamical information in SBDD . 22 3 Methods 25 3.1 X-ray protein crystallography . 25 3.1.1 Crystal symmetry . 26 3.1.2 Diffraction of X-rays by a crystal . 26 3.1.3 Protein crystals . 30 3.1.4 Crystallographic data collection at synchrotron radiation sources 31 i ii CONTENTS 3.1.5 Data processing . 33 3.1.6 The phase problem . 34 3.1.7 Structure refinement and validation . 36 3.2 Molecular dynamics simulations . 36 3.2.1 The equation of motion (EOM) of atoms in a protein . 37 3.2.2 Force field parameters to integrate the EOM . 38 3.2.3 Solvent models . 39 3.3 Molecular docking . 40 3.3.1 Principles . 40 3.3.2 Docking algorithms . 40 3.3.3 Scoring function . 41 3.3.4 Flexible docking . 42 4 Optimization of KM297, a neutral AChE reactivator 43 4.1 Design, synthesis and in vitro evaluation of the reactivator KM297 . 44 4.2 Flexible docking of KM297 into hAChE-VX . 46 4.2.1 Material and methods . 46 4.2.2 Ligand scoring and conformational analysis . 47 4.3 Simulation of hAChE-VX-KM297 . 49 4.3.1 Calculation of force field parameters for OP-inhibited AChE . 49 4.3.2 Optimization of the ligand linker length . 51 4.4 X-ray crystallography . 54 4.4.1 Material and methods . 55 4.4.2 Crystallographic structure determination of the non-aged Tc AChE- tabun conjugate. 59 4.4.3 Crystallographic structure determination of the Tc AChE-KM297 complex . 64 4.4.4 Crystallographic structure determination of non-aged Tc AChE- NEDPA-KM297 complex . 69 4.5 Lead optimization: the JDS family . 74 4.5.1 Docking of chlorinated derivatives of KM297 . 75 4.5.2 Docking of JDS207 . 76 4.5.3 Crystallographic structure determination of TcAChE-JDS207 complex . 77 4.6 Structure determination of native hAChE . 80 4.6.1 Enzyme production . 81 4.6.2 Crystallogenesis . 81 4.6.3 Data collection and processing . 82 4.6.4 Structure refinement . 83 4.6.5 Structural analysis . 83 4.7 Conclusions . 85 CONTENTS iii 5 Building a flexible docking receptor library 89 5.1 Simulations of native AChE . 90 5.1.1 Material and methods . 90 5.1.2 Sampling of side chain conformations in one long versus mul- tiple short simulations . 91 5.1.3 Convergence of the multiple short simulations method . 95 5.1.4 Comparison of human and Torpedo californica AChE dynamics 99 5.2 Generation of receptors library . 102 5.2.1 Extraction of the most probable side chain conformations from MD simulation trajectories . 102 5.2.2 Modification of Tc AChE structure to generate receptors . 104 5.3 Validation of the method: docking routines . 105 5.4 Validation of the method: analysis of the results . 106 5.4.1 Quantitative analysis of docking solutions . 107 5.4.2 Structural analysis of docking solutions . 108 5.4.3 The role of water molecules . 112 5.5 Conclusions . 112 6 General conclusions and perspectives 117 6.1 Design and optimization of KM297 . 117 6.2 Side chains dynamics and flexible docking . 119 6.3 Perspectives . 120 7 Resumé de la thèse en français 123 7.1 Introduction . 123 7.1.1 L’acetylcholinesterase . 123 7.1.2 Conception de médicaments et dynamique des proteines . 124 7.2 Resultats . 125 7.2.1 Conception et optimisation d’un oxime bifonctionel . 125 7.2.2 Developement d’un outil pour le docking flexible . 126 7.3 Conclusions generales . 127 Bibliography 127 A Docking code 149 B Published manuscripts 159 iv CONTENTS List of Figures 1.1 Schematic representation of a neuromuscular junction. AChE is found in the synaptic cleft and restores transmission by hydrolyzing neuro- transmitter acetylcholine (ACh). 4 1.2 The 3-dimensional structure of Tc AChE (Sussman et al., 1991). The catalytic triad is shown in red sticks at the core of the enzyme. In this orientation, the entrance of the active site gorge, whose surface is shown in green, is at the top of the figure. The red squares show the details of the interaction between the substrate analogue OTMA (carbons shown in cyan) and the residues in the gorge of Tc AChE (Colletier et al., 2006a). A) The peripheral aromatic site residues, shown in green at the top of the figure, with a substrate molecule bound in front of Trp279. B) The catalytic site. Bound to the triad, shown in red, we observe a second substrate analogue molecule, cova- lently bound to Ser200. The choline moiety is in cation- π interaction with Trp84 (blue). The oxygen of OTMA is stabilized in the oxyan- ion hole (orange), and the methyl of the acetyl group is nested in the acyl-binding pocket (purple). 6 1.3 Neurotransmitter acetylcholine (a) and its non-hydrolyzable analogue (b) 4-oxo-N,N,N-trimethylpentanaminium (OTMA) . 7 1.4 General structure of an organophosphate nerve agent. 9 1.5 The main organophosphate agents. Molecules of the G-series: tabun (GA), sarin (GB), soman (GD), cyclosarin (GF); and lead molecule of the V-series: VX. 10 1.6 The inhibition mechanism of AChE by organophosphate nerve agents. 11 v vi LIST OF FIGURES 1.7 Crystallographic snapshots of aging of tabun-inhibited mAChE (pdb acces code 3dl4 and 3dl7). We can observe that His447 moves from an alternative conformation forced by the ethoxy substituent of tabun back to its native one, forming a salt bridge with the oxyanion of the phosphoramidyl group corresponding to aged tabun (Millard et al., 1999a; Carletti et al., 2008). 12 1.8 Structures of the most common oximes. 13 1.9 Reactivation mechanism of OP-inhibited AChE by a nucleophile Nu. 13 1.10 General structure of a bifunctional reactivator. It is formed by a group bearing an oxime function and a peripheral site ligand (PSL), connected by a flexible linker.
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