Depuis les années 1990, la chimie combinatoire dynamique permet la découverte et la préparation de nouveaux récepteurs synthétiques à partir de briques moléculaires simples sous contrôle thermodynamique. Dans ce contexte, nous avons récemment décrit une nouvelle famille de para-cyclophanes dynamiques: les dyn[n]arènes. Ces macrocycles, composés de briques moléculaires 1,4-bisthiophénoliques fonctionnalisées, ont pu être obtenus à l'échelle du gramme à partir d'une procédure simple ne mettant pas en jeu de purification par chromatographie. Cette accessibilité synthétique a rendu possible une étude structurale permettant la rationalisation des forces motrices mises en jeu lors des processus d'auto-assemblage, mais aussi de leurs propriétés de reconnaissance moléculaire vis-à-vis de molécules ioniques. A partir de données expérimentales et de calculs réalisés en chimie théorique, les phénomènes physiques responsables de la sélectivité et de l'affinité remarquables observées entre l'un des membres de cette famille, un dyn[4]arène poly anionique, et une série d'a,?-alkyle-diamines ont été étudiés. Finalement, au cours de cette étude, nous avons redécouvert une voie de synthèse simple menant à une famille de molécules encore peu étudiée : les dithiocines. La fonctionnalisation de ces objets a été explorée dans le but d'obtenir une plateforme multifonctionnelle pour des applications biologiques / Since the 1990s, dynamic combinatorial chemistry has allowed the discovery and preparation of new synthetic receptors from simple building blocks under thermodynamic control. In this context, we have recently described a new family of dynamic para cyclophanes, the so-called dyn[n]arenes. These macrocycles, made from functionalized 1,4-bisthiophenolic building blocks, could be obtained on a gram scale from a simple purification procedure, and without any chromatography. Their synthetic accessibility allows us to study the driving forces behind their self-assembly, as well as their molecular recognition properties towards ionic guest molecules. Experimental and computational experiments were also conducted to reveal the subtle physical phenomena that are responsible for the remarkable selectivity and affinity observed between a poly-anionic dyn[4]arene and a series of a,?-alkyl-diamines. During these previous studies, we rediscovered a simple synthetic route towards a family of molecules that is unexploited so far: the dithiocins. The functionalization of these molecular objects has been explored in order to generate versatile platforms for biological applications

Noncovalent interactions are of pivotal importance in many areas of chemistry, biology, and materials science, and the intermolecular interactions involving aromatic rings in particular, are fundamental to molecular organization and recognition processes. The work detailed in this thesis involves the application of state-of-the-art ab initio electronic structure theory methods to elucidate the nature of pi-pi interactions. The binding energies, and geometrical and orientational preferences of the simplest prototype of aromatic pi-pi interactions, the benzene dimer, are explored. We obtain the first converged values of the binding energies using highly accurate methods and large basis sets. Results from this study predict the T-shaped and parallel-displaced configurations of benzene dimer to be nearly isoenergetic. The role of substituents in tuning pi-pi interaction is investigated. By studying dimers of benzene with various monosubstituted benzenes (in the sandwich and two T-shaped configurations), we surprisingly find that all of the substituted sandwich dimers considered bind more strongly than benzene dimer. We also find that these interactions can be tuned by a modest degree of substitution. Energy decomposition analysis using symmetry-adapted perturbation theory (SAPT) reveals that models based solely on electrostatic effects will have difficulty in reliably predicting substituent effects in pi-pi interactions.

Comprendre les interactions réalisées entre un candidat médicament et sa protéine cible est un enjeu crucial pour orienter la recherche de nouvelles molécules. En effet, ce processus implique de nombreux paramètres qu’il est nécessaire d’analyser séparément pour mieux comprendre leurs effets.Nous proposons ici deux nouvelles approches observant les relations protéine/ligand. La première se concentre sur la comparaison de cavités formées par les sites de liaison pouvant accueillir une molécule. Cette méthode permet d’inférer la fonction d’une protéine mais surtout de prédire « l’accessibilité » d’un site de liaison pour un médicament. La seconde tactique se focalise sur la comparaison des interactions non-covalentes réalisées entre la protéine et le ligand afin d’améliorer la sélection de molécules potentiellement actives lors de criblages virtuels, et de rechercher de nouveaux fragments moléculaires, structuralement différents mais partageant le même mode d’interaction. / Understanding the interactions between a drug and its target protein is crucial in order to guide drug discovery. Indeed, this process involves many parameters that need to be analyzed separately to better understand their effects.We propose two new approaches to observe protein/ligand relationships. The first focuses on the comparison of cavities formed by binding sites that can accommodate a small molecule. This method allows to infer the function of a protein but also to predict the accessibility of a binding site for a drug. The second method focuses on the comparison of non-covalent interactions made between the protein and the ligand to improve the selection of potentially active molecules in virtual screening, and to find new molecular fragments, structurally different but sharing the same mode of interaction.

Les interactions non-covalentes ont une importance fondamental pour la chimique. Les interactions entre un catalyseur et le substrat, interactions entre matériaux, synthèse des enantiomers parmi autres réactions chimiques sont décrivent par interactions non-covalentes. Elles sont fondamental pour designer nouveaux matériaux. Les interactions non-covalents sont très suivant visualisées à partir de mesures de contactes atomiques qui utilisent des donnes de rayon de van de Waals. Cette type d'approximations ne sont pas très flexible pour comprendre l'interaction avec l'environnement. Aujourd'hui les approximations qui utilisent des fonctions dans l'espace réel (i.e. la densité électronique) sont très utilisent pour visualiser les interactions non-covalentes. Dans cet thèse, on analyse la méthode NCI pour visualiser interactions chimiques. On analyse les gradient réduit de la densité, ingrédient fondamental dans la méthode NCI. On montré que cette fonction est liée au la densité d'énergie cinétique et au comportement bosonique du système. On montre que la méthode NCI peut être utilisée pour analyser tous les types d'interactions; dès interactions covalentes aux non-covalentes. Finalement la méthode est appliqué à la réactivité chimique. / Non-covalent interactions are of paramount importance in chemistry. Interactions between a catalyst and its substrate, self-assembly of nanomaterials, enantiomer production and many other chemical reactions, are most of the time non-covalent in nature. They are also fundamental for crystallographic analysis, since they set up the scenario for molecular crystallization, whose guiding rules are still a fruitful filed of research. Non-covalent interactions are frequently visualized using distance dependent contacts, generally without consideration of hydrogen atoms. Most of these interactions are usually identified by the use of tabulated van der Waals radii, which are not flexible enough to reveal the interplay with the environment. New approaches, based on 3D functions that can be derived either form experiment or computation (e.g. the electro density) are now widely used to identify and visualize non-covalent interactions. In this thesis we analyse the NCI method, and namely, its main ingredient, the reduced density gradient. Its capabilities for visualizing chemical interactions are examined. This 3D function is then, connected with the kinetic energy density and a interpretation of the reduced density gradient in terms of the bosonic behaviour of the electronic system is presented. Then, the NCI method is applied to visualise and analyse chemical interactions: from covalent to non-covalent interactions. The chemical reactivity is also addressed. The NCI method is applied to rationalised the outcome of several reactions.

The thesis specializes in the computational description of pharmaceutically important compounds. A substantial number of pharmaceutical drugs are small molecules that are bound to an active site of an enzyme by the "lock (binding site) and key (drug)" model through non-covalent interactions. The association of enzymes with drugs cause an increase or decrease in the activity of enzymes. The main topic is focused on the computational elucidation of the structural basis for the interactions of the purine-like compounds with the enzyme cyclin- dependent kinase 2 that belongs to the protein-kinase enzyme family. These enzymes play an important role in the cell cycle regulation; their increased activity significantly contributes to the loss of control over cell proliferation, which is one of the primary causes of cancer cell formation. The study describes the binding motifs of roscovitine, which shows an inhibitory effect on the function of cyclin-dependent kinases, and its analogues containing bioisosteric central heterocycles in the complex with cyclin-dependent kinase 2. The binding affinity between the cyclin-dependent kinase 2 enzyme and the inhibitors was quantified as calculated binding scores and evaluated in relation to the conformation of the optimized structures. The hybrid model combining the...

Studies on interactions between NKR-P1D and Clrb membrane receptors Interaction between murine NKR-P1D and Clrb receptors was originally described as a novel type of "MHC class-I independent missing-self recognition" and was shown to confer protection from killing by natural killer cells.[1] However, further study brought conflicting results suggesting that NKR-P1D does not binds Clrb strongly if it does at all.[2] In order to address the issues arising from these conflicting results, we have recombinantly expressed the extracellular domains of both receptors in E. coli cells and refolded the proteins in vitro. The quality of refolding was confirmed both by determining the disulphide bonding pattern using FTMS and measuring 1 H/15 N-HSQC spectra. By means of size exclusion chromatography and analytical ultracentrifuge we were unable to provide convincing results for the interaction itself. However, using SPR technique, a weak, specific, pH-dependent interaction was observed. Interaction between the proteins in solution was immobilized using chemical cross-linking technique. Three cross-linking reagents, EDC, DSG and DSS were used. The reaction mixture was separated by means of SDS-PAGE and protein bands corresponding to dimers were digested in gel. Using FT-MS we were able to find peptides from both...

Ce manuscrit présente une méthodologie rationnelle de synthèse, caractérisation, détermination de la structure électronique et du comportement dynamique d’espèces bimétalliques électroniquement insaturées de type Cr(0)-M (avec M = Pd(II), Pt(II) ou Rh(I)). Ces nouvelles espèces constituent de rares exemples d’entités électro-insaturées à 14 électrons ayant la spécificité d’être persistantes en solution. Leur cohésion structurale provient essentiellement de la compensation d’un faible caractère de type donneur/accepteur entre les deux métaux par des interactions non-covalentes Coulombiennes. Nous montrons ainsi qu’en tirant profit du caractère ambiphile d’un ligand hétéroditopique capable de chélater un centre métallique par l’établissement d’une liaison covalente et d’une interaction non-covalente, de nouvelles espèces coordinativement insaturées peuvent être obtenues. Nous proposons d’appeler ce nouveau mode de chelation : « Hemichelation ». / The present manuscript will present a rational method of synthesis, characterization, determination of the electronic structure and dynamic behaviour of solution-persistent, and formally unsaturated binuclear Cr(0)-M complexes (with M= Pd(II), Pt(II) or Rh(I)). This new class of complexes constitutes rare examples of persistent coordinatively unsaturated 14-electrons complexes, whose cohesion stems essentially from a compensation of insufficient donor/acceptor Cr-M bonding by non-covalent interactions of preponderant attractive Coulombic nature. By taking advantage of the ambiphilic character of a heteroditopic ligand capable of chelating a metal centre through covalent and noncovalent bonds, truly coordination-unsaturated complexes can be synthesized in a manageable form. We propose to name “Hemichelation” the half-covalent/half noncovalent bonding-relationship between the ambiphilic heteroditopic ligand and the electron-unsaturated metallic centre.

Background: Structure-based drug repositioning has emerged as a promising alternative to conventional drug development. Regardless of the many success stories reported over the past years and the novel breakthroughs on the AI-based system AlphaFold for structure prediction, the availability of structural data for protein–drug complexes remains very limited. Whereas the chemical libraries contain millions of drug compounds, the vast majority of them do not have structures to crystallized targets,and it is, therefore, impossible to characterize their binding to targets from a structural view. However, the concept of building blocks offers a novel perspective on the structural problem. A drug compound is considered a complex of small chemical blocks or fragments, which confer the relevant properties to the drug and have a high proportion of functional groups involved in protein binding. Based on this, we propose a novel approach to expand the scope of structure-based repositioning approaches by transferring the structural knowledge from a fragment to a compound level. - Results: We fragmented over 100,000 compounds in the Protein Data Bank (PDB) and characterized the structural binding mode of 153,000 fragments to their crystallized targets. Using the fragment’s data, we were able to artificially reconstruct the binding mode of over 7,800 complexes between ChEMBL compounds and their known targets, for which no structural data is available. We proved that the conserved binding tendency of fragments, when binding to the same targets, highly influences the drug’s binding specificity and carries the key information to reconstruct full drugs binding mode. Furthermore, our approach was able to reconstruct multiple compound-target pairs at optimal thresholds and high similarity to the actual binding mode. - Conclusions: Such reconstructions are of great value and benefit structure-based drug repositioning since they automatically enlarge the technique’s scope and allow exploring the so far ‘unexplored compounds’ from a structural perspective. In general, the transfer of structural information is a promising technique that could be applied to any chemical library, to any compound that has no crystal structure available in PDB, and even to transfer any other feature that may be relevant for the drug discovery process and that due to data limitations is not yet fully available. In that sense, the results of this work document the full potential of structure-based screening even beyond PDB.

Non-covalent interactions including nucleobase hydrogen bonding and phosphonium/ammonium ionic aggregation were studied in block and random polymers synthesized using controlled radical polymerization techniques such as nitroxide mediated polymerization (NMP) and reversible addition-fragmentation chain transfer polymerization (RAFT). Non-covalent interactions were expected to increase the effective molecular weight of the polymeric precursors through intermolecular associations and to induce microphase separation. The influence of non-covalent association on the structure/property relationships of these materials were studied in terms of physical properties (tensile, DMA, rheology) as well as morphological studies (AFM, SAXS). Ionic interactions, which possess stronger interaction energies than hydrogen bonds (~150 kJ/mol) were studied in the context of phosphonium-containing acrylate triblock (ABA) copolymers and random copolymers. Phosphonium-containing ionic liquid monomers with different alkyl substituent lengths and counterions enabled an investigation of the effects of ionic aggregation of phosphonium cations on the polymer physical properties. The polymerization of styrenic phosphonium-containing ionic liquid monomers using a difunctional alkoxyamine initiator, DEPN2, afforded an ABA triblock copolymer with an n-butyl acrylate soft center block and symmetric phosphonium-containing external reinforcing blocks. Small-angle X-ray scattering (SAXS) and transmission electron microscopy (TEM) of triblock copolymers revealed pronounced microphase separation at the nanoscale. Phosphonium aggregation governed block copolymer flow activation energies. In random copolymers, the phosphonium cations only weakly aggregated, which strongly depended on the length of alkyl substituents and the type of counterions. Acrylate random copolymers consisting of quaternary ammonium functionalities were synthesized using reversible addition-fragmentation chain transfer polymerization (RAFT). The obtained copolymers possessed controlled compositions and narrow molecular weight distributions with molecular weights ranging from Mn =50,000 to 170,000 g/mol. DMA evidenced the weak aggregation of ammonium cations in the solid state. Additionally, this ionomer was salt-responsive in NaCl aqueous solutions. Hydrogen bonding, a dynamic interaction with intermediate enthalpies (10-40 kJ/mol) was introduced through complementary heterocyclic DNA nucleobases such as adenine, thymine and uracil. Our investigations in this field have focused on the use of DNA nucleobase pair interactions to control polymer self-assembly and rheological behavior. Novel acrylic adenine- and thymine-containing monomers were synthesized from aza-Michael addition reaction. The long alkyl spacers between nucleobase and polymer backbone afforded structural flexibility in self-assembly process. Adenine-containing polyacrylates exhibited unique morphologies due to adenine-adenine π-π interactions. The complementary hydrogen bonding of adenine and thymine resulted in disruption of adenine-adenine π-π interactions, leading to lower plateau modulus and lower softening temperatures. Moreover, hydrogen bonding interactions enabled the compatibilization of complementary hydrogen bonding guest molecules such as uracil phosphonium chloride. / Ph. D.

The fidelity of biological processes and reactions, inspite of the widespread diversity, is programmed by highly specific physico-chemical principles. This underlines our basic understanding of different interesting phenomena of biological relevance, ranging from enzyme specificity to allosteric communication, from selection of fold to structural organization / states of oligomerization, from half-sites-reactivity to reshuffling of the conformational free energy landscape, encompassing the dogma of sequence-structure dynamics-function of macromolecules. The role of striking an optimal balance between rigidity and flexibility in macromolecular 3D structural organisation is yet another concept that needs attention from the functional perspective. Needless to say that the variety of protein structures and conformations naturally leads to the diversity of their function and consequently many other biological functions in general. Classical models of allostery like the ‘MWC model’ or the ‘KNF model’ and the more recently proposed ‘population shift model’ have advanced our understanding of the underlying principles of long range signal transfer in macromolecules. Extensive studies have also reported the importance of the fold selection and 3D structural organisation in the context of macromolecular function. Also ligand induced conformational changes in macromolecules, both subtle and drastic, forms the basis for controlling several biological processes in an ordered manner by re-organizing the free energy landscape. The above mentioned biological phenomena have been observed from several different biochemical and biophysical approaches. Although these processes may often seem independent of each other and are associated with regulation of specialized functions in macromolecules, it is worthwhile to investigate if they share any commonality or interdependence at the detailed atomic level of the 3D structural organisation. So the nagging question is, do these diverse biological processes have a unifying theme, when probed at a level that takes into account even subtle re-orchestrations of the interactions and energetics at the protein/nucleic acid side-chain level. This is a complex problem to address and here we have made attempts to examine this problem using computational tools. Two methods have been extensively applied: Molecular Dynamics (MD) simulations and network theory and related parameters. Network theory has been extensively used in the past in several studies, ranging from analysis of social networks to systems level networks in biology (e.g., metabolic networks) and have also found applications in the varied fields of physics, economics, cartography and psychology. More recently, this concept has been applied to study the intricate details of the structural organisation in proteins, providing a local view of molecular interactions from a global perspective. On the other hand, MD simulations capture the dynamics of interactions and the conformational space associated with a given state (e.g., different ligand-bound states) of the macromolecule. The unison of these two methods enables the detection and investigation of the energetic and geometric re-arrangements of the 3D structural organisation of macromolecule/macromolecular complexes from a dynamical or ensemble perspective and this has been one of the thrust areas of the current study. So we not only correlate structure and functions in terms of subtle changes in interactions but also bring in conformational dynamics into the picture by studying such changes along the MD ensemble. The focus was to identify the subtle rearrangements of interactions between non-covalently interacting partners in proteins and the interacting nucleic acids. We propose that these rearrangements in interactions between residues (amino acids in proteins, nucleic acids in RNA/DNA) form the common basis for different biological phenomena which regulates several apparently unrelated processes in biology. Broadly, the major goal of this work is to elucidate the physico-chemical principles underlying some of the important biological phenomena, such as allosteric communication, ligand induced modulation of rigidity/flexibility, half-sites-reactivity and so on, in molecular details. We have investigated several proteins, protein-RNA/DNA complexes to formulate general methodologies to address these questions from a molecular perspective. In the process we have also specifically illuminated upon the mechanistic aspects of the aminoacylation reaction by aminoacyl-tRNA synthetases like tryptophanyl and pyrrolysyl tRNA synthetase, structural details related to an enzyme catalyzed reaction that influences the process of quorum sensing in bacteria. Further, we have also examined the ‘dynamic allosterism’ that manipulates the activity of MutS, a prominent component of the DNA bp ‘mismatch repair’ machinery. Additionally, our protein structure network (PSN) based studies on a dataset of Rossmann fold containing proteins have provided insights into the structural signatures that drive the adoption of a fold from a repertoire of diverse sequences. Ligand induced percolations distant from the active sites, which may be of functional relevance have also been probed, in the context of the S1A family of serine proteases. In the course of our investigation, we have borrowed several concepts of network parameters from social network analysis and have developed new concepts. The Introduction (Chapter-1) summarizes the relevant literature and lays down a suitable background for the subsequent chapters in the thesis. The major questions addressed and the main goal of this thesis are described to set an appropriate stage for the detailed discussions. The methodologies involved are discussed in Chapter-2. Chapter-3 deals with a protein, LuxS that is involved in the bacterial quorum sensing; the first part of the chapter describes the application of network analysis on the static structures of several LuxS proteins from different organisms and the second part of this chapter describes the application of a dynamic network approach to analyze the MD trajectories of H.pylori LuxS. Chapter-4 focuses on the investigation of human tryptophanyl-tRNA synthetase (hTrpRS), with an emphasis to identify ligand induced subtle conformational changes in terms of the alternation of rigidity/flexibility at different sites and the re-organisation of the free energy landscape. Chapter-5 presents a novel application of a quantum clustering (QC) technique, popular in the fields of pattern recognition, to objectively cluster the conformations, sampled by molecular dynamics simulations performed on different ligand bound structures of the protein. The protein structure network (PSN) in the earlier studies were constituted on the basis of geometric interactions. In Chapters 6 and 7, we describe the networks (proteins+nucleic acids) using interaction energy as edges, thus incorporating the detailed chemistry in terms of an energy-weighted complex network. Chapter-6 describes an application of the energy weighted network formalism to probe allosteric communication in D.hafniense pyrrolysyl-tRNA synthetase. The methodology developed for in-depth study of ligand induced changes in DhPylRS has been adopted to the protein MutS, the first ‘check-point protein’ for DNA base pair (bp) mismatch repair. In Chapter-7, we describe the network analysis and the biological insights derived from this study (the work is done in collaboration with Prof. David Beveridge and Dr. Susan Pieniazek). Chapter-8 describes the application of a network approach to capture the ligand-induced subtle global changes in protein structures, using a dataset of high resolution structures from the S1A family of serine proteases. Chapter-9 deals with probing the structural rationale behind diverse sequences adopting the same fold with the NAD(P)-binding Rossmann fold as a case study. Future directions are discussed in the final chapter of the thesis (Chapter-10).