Quenched Molecular Dynamics (QMD) used to explore molecular conformations was developed to operate in Insight II platform for two simulation engines: CHARMm and Discover. Two scripts and procedures were written for molecular minimization, dynamics, minimization of each of several hundred conformers, and cut off. Experience with Insight II/Discover versus Quanta/CHARMm, and between Insight II/CHARMm versus Quanta/CHARMm has taught that the forcefield is the key factor in QMD studies. Protein A has been used for the purification of commercial antibodies, but it is expensive. Seven peptidomimetics of protein A were designed based on the hot-spots located at the helix-loop-helix region of protein A, and synthesized via solid phase using the Fmoc approach. These peptidomimetics were characterized by MS and NMR. The conformations of four peptidomimetics were studied by NMR and CD in water/hexafluoroisopropanol (pH 4). The CD and NMR data show that addition of hexafluoroisopropanol stabilizes their a-helical conformations. The structures of these peptidomimetics in solution were generated with Quanta/CHARMm using NMR data as limits for the QMD technique. Protein G has also been used to purify antibodies, but it is expensive too. A number of protein G mimics were designed as trivalent molecules. An efficient preparation of trivalent molecules having a useful primary amine arm has been developed through solid phase synthesis. The cheap, commercially available poly(propylene imine) dendrimers were used as scaffolds which allow multimerization of functionalized compounds. A small library of trivalent compounds were synthesized using this approach. A portion of compounds in this library were tested by Amersham Biosciences. The seven amino acid modified DAB-Am-4 exhibits strong binding to the IgG/Fab, and is a potential ligand for IgG purification. The interactions between neurotrophins (ie NGF and NT-3) and their receptors are typical drug targets. Fourteen second-generation peptidomimetics showing NGF-like or NT3-like activities in a preliminary bioassay, were resynthesized and tested again. Preliminary and retested data were compared. To access a direct binding assay, five fluorescently labeled peptidomimetics 41a-e were synthesized for a fluorescence activated cell sorting (FACScan) assay. Six monomeric precursors 42 and 43 were prepared on large scales for the library of bivalent turn analogs

Quenched Molecular Dynamics (QMD) used to explore molecular conformations was developed to operate in Insight II platform for two simulation engines: CHARMm and Discover. Two scripts and procedures were written for molecular minimization, dynamics, minimization of each of several hundred conformers, and cut off. Experience with Insight II/Discover versus Quanta/CHARMm, and between Insight II/CHARMm versus Quanta/CHARMm has taught that the forcefield is the key factor in QMD studies. Protein A has been used for the purification of commercial antibodies, but it is expensive. Seven peptidomimetics of protein A were designed based on the hot-spots located at the helix-loop-helix region of protein A, and synthesized via solid phase using the Fmoc approach. These peptidomimetics were characterized by MS and NMR. The conformations of four peptidomimetics were studied by NMR and CD in water/hexafluoroisopropanol (pH 4). The CD and NMR data show that addition of hexafluoroisopropanol stabilizes their a-helical conformations. The structures of these peptidomimetics in solution were generated with Quanta/CHARMm using NMR data as limits for the QMD technique. Protein G has also been used to purify antibodies, but it is expensive too. A number of protein G mimics were designed as trivalent molecules. An efficient preparation of trivalent molecules having a useful primary amine arm has been developed through solid phase synthesis. The cheap, commercially available poly(propylene imine) dendrimers were used as scaffolds which allow multimerization of functionalized compounds. A small library of trivalent compounds were synthesized using this approach. A portion of compounds in this library were tested by Amersham Biosciences. The seven amino acid modified DAB-Am-4 exhibits strong binding to the IgG/Fab, and is a potential ligand for IgG purification. The interactions between neurotrophins (ie NGF and NT-3) and their receptors are typical drug targets. Fourteen second-generation peptidomimetics showing NGF-like or NT3-like activities in a preliminary bioassay, were resynthesized and tested again. Preliminary and retested data were compared. To access a direct binding assay, five fluorescently labeled peptidomimetics 41a-e were synthesized for a fluorescence activated cell sorting (FACScan) assay. Six monomeric precursors 42 and 43 were prepared on large scales for the library of bivalent turn analogs

Mon travail de thèse, concernant les collisions centrales Au+Au entre 40 et 100 MeV/A, se place dans le cadre d'une analyse comprenant le dépouillement et l'interprétation des résultats de la 4ème campagne de mesure du multidétecteur INDRA. La première phase de cette étude, dite de "dépouillement", a permis de reconstruire, à partir des données brutes des deux premiers étages de détection d'INDRA (chambre d'ionisation, Silicium), les énergies cinétiques et la charge des fragments détectés. Pour la première fois, il a été possible de mettre en évidence et de corriger les effets de non-linéarité dans la chaîne d'acquisition <br />d'INDRA. A l'issue de ce travail, je me suis attaché à selectionner les collisions centrales. <br />Pour ce faire, et dans le souci de ne pas biaiser les interprétations physiques résultantes, j'ai mis en oeuvre deux méthodes distinctes: sélection en paramètre d'impact ainsi qu'une analyse en composante principale. Une étude comparative de ces deux outils mathématiques a été entreprise donnant lieu à des résultats très instructifs.<br /><br /><br />L'interprétation des résultats a fait appel à plusieurs types de modèles lesquels impliquant la validité de certaines hypothèses (équilibre thermodynamique, existence d'un volume de "freeze-out"). L'emploi de modèles statistiques (SMM, MMMC) a permis <br />d'extraire la taille du système émetteur, dit "source unique", ainsi que son énergie d'excitation. L'anisotropie des distributions en énergie cinétiques des fragments, a permis de <br />mettre en évidence, en fonction de l'énergie incidente de la collision, une déformation de la source, mais également de reconstruire les énergies thermique et collective entrant en jeu. Une nouvelle comparaison des données à l'aide de modèles dits "dynamique" (QMD,CMD) a été également entreprise. A l'issu de cette étude, des critiques portant sur la validité d'une approche telles SMM ou MMMC ont pu être émises remettant en jeu le fondement de l'interprétation physique du flot collectif couramment employé.