Lecture_18 - Protein Structure Determination Protein Folding Molecular Chaperones Prions Alzyheimers Tertiary Structure of Proteins Two methods 1

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Protein Structure Determination Protein Folding Molecular Chaperones Prions Alzyheimer’s
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Tertiary Structure of Proteins Two methods: 1. X-RAY diffraction crystal structure 2. NMR solution structure This is a crystal X-ray diffraction pattern of sperm whale myoglobin
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Electron density map 6 Å 2.0 Å 1.5 Å 1.1 Å From the diffraction pattern (spots and intensity) one can get a mathematical description of the electron density of a molecule. With proper model construction a 3-D image of the protein is constructed.
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NMR
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By using chemical shifts of backbone hydrogens and their chemical splitting bond angles can be determined. COSY NMR or Correlated Spectroscopy. By manipulating parameters protons that are close to each other in space but not linked through bonds can be determined by NOSY NMR or Nuclear Overhauser spectroscopy. Growing the protein in bacteria where the carbon source can be substituted by 13 C and the nitrogen by 15 N (stable isotope substitution) more restraints can be achieved. The liquid structure(s) can be determined as a group that fit a certain structure space.
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Quaternary Structure and Symmetry Subunits can associate noncovalently, subunits are protomers if identical . Protomer subunits are symmetrically arranged Only rotational symmetry allowed. i.e. cyclic symmetry C2, C3, C6 etc. Dihedral symmetry N-fold intersects a two-fold rotational symmetry at right angles Other higher order types, octahedral or tetrahedral
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Protein folding is “one of the great unsolved problems of science” Alan Fersht
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protein folding can be seen as a connection between the genome (sequence) and what the proteins actually do (their function).
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Protein folding problem Prediction of three dimensional structure from its amino acid sequence Translate “Linear” DNA Sequence data to spatial information
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Why solve the folding problem? Acquisition of sequence data relatively quick Acquisition of experimental structural information slow Limited to proteins that crystallize or stable in solution for NMR
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Protein folding dynamics Electrostatics, hydrogen bonds and van der Waals forces hold a protein together. Hydrophobic effects force global protein conformation. Peptide chains can be cross-linked by disulfides, Zinc, heme or other liganding compounds. Zinc has a complete d orbital , one stable oxidation state and forms ligands with sulfur, nitrogen and oxygen. Proteins refold very rapidly and generally in only one stable conformation.
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The sequence contains all the information to specify 3-D structure
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Random search and the Levinthal paradox The initial stages of folding must be nearly random, but if the entire process was a random search it would require too much time. Consider a 100 residue protein. If each residue is considered to have just 3 possible conformations the
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This note was uploaded on 02/22/2011 for the course BCHS 3304 taught by Professor Johnson during the Spring '08 term at University of Houston.

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Lecture_18 - Protein Structure Determination Protein Folding Molecular Chaperones Prions Alzyheimers Tertiary Structure of Proteins Two methods 1

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