Peptidomimetics to mimic protein-protein interactions

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Title: Peptidomimetics to mimic protein-protein interactions
Author: Xia, Zebin
Abstract: 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
URI: http : / /hdl .handle .net /1969 .1 /2239
Date: 2005-08-29


Peptidomimetics to mimic protein-protein interactions. Available electronically from http : / /hdl .handle .net /1969 .1 /2239 .

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