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

• Published in: Pharmaceutica acta Helvetiae Vol. 71; no. 1; pp. 37 - 44
• Main Authors: Günther, Gero, Fechteler, Till, Villmann, Carmen, Zakaria, Hayssam, Schomburg, Dietmar, Otto, Bernd
• Format: Journal Article
• Language: English
• Published: Switzerland Elsevier B.V 01.06.1996
• Subjects: Amino Acid Sequence; Computer modeling; Computer Simulation; Disulfide bridges; Disulfides - chemistry; Humans; Interferon; Interferon-gamma - chemistry; Models, Structural; Molecular Sequence Data; Recombinant Proteins; Interferon; Computer modeling; Disulfide bridges
• ISSN: 0031-6865
• DOI: 10.1016/0031-6865(95)00045-3

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 ‘Ssuitable’ was written for this purpose. This methodological approach was applied to recombinant human interferon-γ (rhu-IFN-γ), a cytokine of great pharmaceutical interest with a wide variety of biological activities including antiviral, antiproliferative and immunomodulatory effects. A model based on the CMα-coordinates obtained from the Brookhaven data base was built. Four different insertion sites were selected in the model, connecting the two subunits of the homodimer. The thermodynamic stability of rhu-IFN-γ is low, limiting its clinical application. We expect that the insertion of additional new disulfide bonds will enhance the thermodynamic stability as well as protect the protein against proteolytic degradation.