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Computer-aided modeling of structure stabilizing disulfide bonds in recombinant human interferon-gamma

: Günther, G.; Fechteler, T.; Villmann, C.; Zakaria, H.; Schomburg, D.; Otto, B.


Pharmaceutica acta Helvetiae 71 (1996), Nr.1, S.37-44
ISSN: 0031-6865
Fraunhofer ITA ( ITEM) ()
computer simulation; disulfide; genetic recombination; human; interferon; interferon gamma; molecular biology

We present a general search algorithm for possible insertion sites of disulfide bonds in proteins based on the coordinates of the solved X-ray or NMR structure, allowing the insertion of disulfide bonds with a minimum of conformational tension and backbone rearrangements. The FORTRAN 77 program "Suitable" was written for this purpose. THis methodological approach was applied to recombinant human interferon gamma (rhu-IFN-gamma), a cytokine of great pharmaceutical interest with a wide variety of biological activities including antiviral, antiproliferative and immunomodulatory effects. A model based on teh C alpha-coordinates obtained from the Brookhaven data base was built. Four different insertion sites were selected in the model, connectinag the two subunits of the homodimer. The thermodynamic stability of rhu-IFN-gamma is low, limiting its clinical application.