Synthesis, electronic and photophysical properties of a bisacridinium-Zn(II) porphyrin conjugate

The synthesis of a novel bisacridinium-Zn(II) porphyrin is reported and its properties investigated via electrochemical, photophysical and computational studies. Cyclic voltammetry studies revealed a two-electron oxidation of the Zn(II) porphyrin and the simultaneous one electron reductions of the two acridiniums. Using absorption, emission and ultrafast transient absorption spectroscopies, the near total fluorescence quenching observed following excitation of either the acridinium or Zn(II) porphyrin units was assigned to ultrafast electron transfer (${\le }0.3$ ps) leading to a reduced acridinium and an oxidized porphyrin unit in the bisacridinium-Zn(II) porphyrin conjugate. In addition, computational studies were found to complement experimental results, with calculations revealing two near degenerate HOMOs for the porphyrin

Synthesis, electronic and photophysical properties of a bisacridinium-Zn(II) porphyrin conjugate

The synthesis of a novel bisacridinium-Zn(II) porphyrin is reported and its properties investigated via electrochemical, photophysical and computational studies. Cyclic voltammetry studies revealed a two-electron oxidation of the Zn(II) porphyrin and the simultaneous one electron reductions of the two acridiniums. Using absorption, emission and ultrafast transient absorption spectroscopies, the near total fluorescence quenching observed following excitation of either the acridinium or Zn(II) porphyrin units was assigned to ultrafast electron transfer (${\le }0.3$ ps) leading to a reduced acridinium and an oxidized porphyrin unit in the bisacridinium-Zn(II) porphyrin conjugate. In addition, computational studies were found to complement experimental results, with calculations revealing two near degenerate HOMOs for the porphyrin

Exploration computationnelle de complexes hôte-invité

Supramolecular chemistry has experienced enormous growth in recent years. Supramolecular processes and, in particular, host-guest interactions are studied for the variety of their potential applications (from industrial processes to medical field application). At the moment, breakthrough discoveries in molecular host-guest chemistry are hampered by the complexity of the thermodynamic and kinetic characterization of the inclusion/release processes, which make it difficult to generate useful predictions about molecular encapsulation.In this context, this thesis project focused on the development of a computational platform for binding free energy prediction of host-guest complexes using both thermodynamic-based and knowledge-based approaches. The aim is not only to improve the overall knowledge in the field of supramolecular chemistry but also to provide new opportunities and applications for existing containers and provide direction in their rational development.Ces dernières années, la chimie supramoléculaire a connu un énorme essor. Les processus supramoléculaires et, en particulier, les interactions hôte-invité sont étudiées pour la variété des applications possibles (des processus industriels au domaine médical). Actuellement, les découvertes dans le domaine de la chimie supramoléculaire hôte-invité sont entravées par la complexité de la caractérisation thermodynamique et cinétique des processus d'inclusion/libération, ce qui rend difficile la génération de prédictions utiles pour l'encapsulation moléculaire.Dans ce contexte, ce projet de thèse s'est concentré sur le développement d'une plateforme de calcul pour la prédiction de l'énergie libre de Gibbs de complexes hôte-invité en utilisant deux approches différentes : la première basée sur la prédiction des paramètres thermodynamiques et la seconde basée sur les connaissances. L'objectif est non seulement d'améliorer les connaissances globales dans le domaine de la chimie supramoléculaire, mais également de fournir de nouvelles opportunités et applications pour les conteneurs existants de manière à aider au développement de ces derniers

Exploration computationnelle de complexes hôte-invité

Ces dernières années, la chimie supramoléculaire a connu un énorme essor. Les processus supramoléculaires et, en particulier, les interactions hôte-invité sont étudiées pour la variété des applications possibles (des processus industriels au domaine médical). Actuellement, les découvertes dans le domaine de la chimie supramoléculaire hôte-invité sont entravées par la complexité de la caractérisation thermodynamique et cinétique des processus d'inclusion/libération, ce qui rend difficile la génération de prédictions utiles pour l'encapsulation moléculaire.Dans ce contexte, ce projet de thèse s'est concentré sur le développement d'une plateforme de calcul pour la prédiction de l'énergie libre de Gibbs de complexes hôte-invité en utilisant deux approches différentes : la première basée sur la prédiction des paramètres thermodynamiques et la seconde basée sur les connaissances. L'objectif est non seulement d'améliorer les connaissances globales dans le domaine de la chimie supramoléculaire, mais également de fournir de nouvelles opportunités et applications pour les conteneurs existants de manière à aider au développement de ces derniers.Supramolecular chemistry has experienced enormous growth in recent years. Supramolecular processes and, in particular, host-guest interactions are studied for the variety of their potential applications (from industrial processes to medical field application). At the moment, breakthrough discoveries in molecular host-guest chemistry are hampered by the complexity of the thermodynamic and kinetic characterization of the inclusion/release processes, which make it difficult to generate useful predictions about molecular encapsulation.In this context, this thesis project focused on the development of a computational platform for binding free energy prediction of host-guest complexes using both thermodynamic-based and knowledge-based approaches. The aim is not only to improve the overall knowledge in the field of supramolecular chemistry but also to provide new opportunities and applications for existing containers and provide direction in their rational development

Highlighting the Major Role of Cyclin C in Cyclin-Dependent Kinase 8 Activity through Molecular Dynamics Simulations

International audienceDysregulation of cyclin-dependent kinase 8 (CDK8) activity has been associated with many diseases, including colorectal and breast cancer. As usual in the CDK family, the activity of CDK8 is controlled by a regulatory protein called cyclin C (CycC). But, while human CDK family members are generally activated in two steps, that is, the binding of the cyclin to CDK and the phosphorylation of a residue in the CDK activation loop, CDK8 does not require the phosphorylation step to be active. Another peculiarity of CDK8 is its ability to be associated with CycC while adopting an inactive form. These specificities raise the question of the role of CycC in the complex CDK8–CycC, which appears to be more complex than the other members of the CDK family. Through molecular dynamics (MD) simulations and binding free energy calculations, we investigated the effect of CycC on the structure and dynamics of CDK8. In a second step, we particularly focused our investigation on the structural and molecular basis of the protein–protein interaction between the two partners by finely analyzing the energetic contribution of residues and simulating the transition between the active and the inactive form. We found that CycC has a stabilizing effect on CDK8, and we identified specific interaction hotspots within its interaction surface compared to other human CDK/Cyc pairs. Targeting these specific interaction hotspots could be a promising approach in terms of specificity to effectively disrupt the interaction between CDK8. The simulation of the conformational transition from the inactive to the active form of CDK8 suggests that the residue Glu99 of CycC is involved in the orientation of three conserved arginines of CDK8. Thus, this residue may assume the role of the missing phosphorylation step in the activation mechanism of CDK8. In a more general view, these results point to the importance of keeping the CycC in computational studies when studying the human CDK8 protein in both the active and the inactive form