Lectures 6 7 -Protein_Folding

Introducing cavities in the core by mutations such as

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-introducing cavities in the core by mutations such as Ile Val or Phe Leu Cavity for a CH2 Stability by 1kcal/mol -More delicate design -Needs structure
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Prediction of Structure From Sequence • Empirical – in progress • ~70% successful-at best (62-65%) • Essence: Pattern Recognition • Key: Evolutionary Information – Sequence homology implies similarity in structure and function – By inference/By Anaysis • Data bases (2007 >500,000 seq., >45,000 Structures Information Prediction • Example: Homologous proteins Conserved Core Variable Loop
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Secondary Structure Prediction for 3-Model • Predict: α, β, loop, β-turn • Predict: membrane-spanning α-helix • Predict: Amphipatic structures αβ • Prediction of the folded structure of tryptophan synthetase, and • the catalytic subunit of c-AMP dependent protein kinase
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Chou & Fassman (1974) • Frequency of occurrence of a given a.a. in α, β, and loops in all protein structures in the database (statistical) • Nearest neighbors output: probability for each residue to be in α, β, or Loop • Artificial intelligence/neural networks – Train a computer to recognize patterns – the more information and the “more practice” the higher the accuracy (in progress)
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Design • Minibody • Chymohelizyme • Calcium channel
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Minibody • Synthetic (61 a.a.) • All β • Template: heavy chain, variable domain of IgG • Hypervariable loops • Binding site: Histidines in each hypervariable loop • Protein it folds and in binds metal (Zn +2 )
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Chymohelizyme (Science 248: 1544, 1990) • Design (computer based): 4 helices, parallel, amphipathic, serine protease • Catalytic TRIAD – Ser, His, Asp at the N-end of the bundle in the same spatial arrangement as chymotrypsin • “oxyanion hole” and substrate binding pocket for acetyl tyrosine ethyl ester, a classical substrate of CT were included in the design • Synthetic enzyme is catalytically active and inhibitor-specific
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introducing cavities in the core by mutations such as Ile...

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