Modification of protein stability by introduction of disulfide bridges and prolines: geometric criteria for mutation sites.
We define geometrical parameters to characterize disulfide bridges using x-ray crystal structure data on small molecules and use them to suggest replacements of amino acids by cysteines in order to introduce disulfide bridges to increase thermal stability in proteins. We also define geometric parameters to identify target amino acids for replacements by prolines in order to conserve desired structural attributes in the vicinity of disulfide mutations leading to further structural and thermal stability of proteins. The geometric criteria are applied to the serine protease, subtilisin, to model stereochemically favorable disulfide mutants without altering the active site geometry, implying conservation of native biological activity.
Balaji
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Discovery Research, Allergan Pharmaceuticals Inc., Irvine, CA 92715.
Mobasser
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Rao
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D001665:Binding Sites; D003460:Crystallization; D004220:Disulfides; D004355:Drug Stability; D015394:Molecular Structure; D009154:Mutation; D011392:Proline; D011487:Protein Conformation; D011506:Proteins; D013329:Structure-Activity Relationship; D013381:Subtilisins / Q000235:genetics; D014961:X-Ray Diffraction
D004220:Disulfides; D011506:Proteins; D011392:Proline; D013381:Subtilisins