Protein folding, Dynamics & Structural Evolution

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11 Terms

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protein structures can be determined at atomic resolutions by x-ray crystallography and NMR

the structure is not rigid, there are always fluctuations in the structure over time, i.e proteins are dynamic

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the information specifying how a protein folds from an extended chain to its native structure is

contained in its primary a.a sequence

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Christian Anfinsen (1957) for ribonuclease a

  1. denature RNaseA in 8M urea (abolishes hydrophobic effect) and BME (reduces disulfide bridges)

  2. remove urea by dialysis then expose to O2 → 100% enzymatic activity recovered

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proteins can follow various folding pathways

forming partially folded conformations with increasing specific structure, until they reach their native state

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energy decreases as folding proceeds

complex energy landscape for folding

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often proteins do not fold or refold efficently → other proteins can promote folding

  1. protein disulfide isomerases: assist in forming correct disulfide bonds

  2. proline cis-trans isomerases: accelerate slow interconversion of cis and trans conformations or peptide bonds involving Pro

  3. folding chaperones e.g (GroEL-GroES)

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GroEL subunits associate to form a dimer of heptamers, hydrophic patches on misfolded proteins bind to hydrophobic surfaces on GroEL

GroES subunits also form a heptamer, which binds to GroEL heptamer after substrate and ATP are bound. this triggers release of misfolded protein into the central cavity, and hydrophobic surfaces of GroEL associate with GRoES

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cycles of ATP binding and hydrolysis drive conformational changes in GRoEL/ES according to

  1. 7 ATP and 1 misfolded protein bind to a GroEL ring

  2. GroES ring binds to the GRoEL ring with bound protein, central cavity further expands, misfolded protein is released into cavity

  3. slow ATP hydrolysis allows time for protein folding

  4. additional misfolded protein and ATP bind to the other GroEL heptamer

  5. binding stimulates release of GroES, ADP and better folded protein

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secondary structure prediction

  1. 50% accurate when based on physical properties

  2. 75% accurate when related (homologous) sequences are also considered

    • limited accuracy b/c tertiary structure and function influence secondary structure

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tertiary structure prediction

  1. homology modeling: model unknown sequence onto known structure of homolgous protein

  2. Ab initio prediction: from chemical principles, and statistics of conformations of stretches of amino acids in known structures

    • e.g Rosetta@home

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structural evolution

a common mechanism of protein evolution is duplication of a protein sequence, followed by gradual