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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
the information specifying how a protein folds from an extended chain to its native structure is
contained in its primary a.a sequence
Christian Anfinsen (1957) for ribonuclease a
denature RNaseA in 8M urea (abolishes hydrophobic effect) and BME (reduces disulfide bridges)
remove urea by dialysis then expose to O2 → 100% enzymatic activity recovered
proteins can follow various folding pathways
forming partially folded conformations with increasing specific structure, until they reach their native state
energy decreases as folding proceeds
complex energy landscape for folding
often proteins do not fold or refold efficently → other proteins can promote folding
protein disulfide isomerases: assist in forming correct disulfide bonds
proline cis-trans isomerases: accelerate slow interconversion of cis and trans conformations or peptide bonds involving Pro
folding chaperones e.g (GroEL-GroES)
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
cycles of ATP binding and hydrolysis drive conformational changes in GRoEL/ES according to
7 ATP and 1 misfolded protein bind to a GroEL ring
GroES ring binds to the GRoEL ring with bound protein, central cavity further expands, misfolded protein is released into cavity
slow ATP hydrolysis allows time for protein folding
additional misfolded protein and ATP bind to the other GroEL heptamer
binding stimulates release of GroES, ADP and better folded protein
secondary structure prediction
50% accurate when based on physical properties
75% accurate when related (homologous) sequences are also considered
limited accuracy b/c tertiary structure and function influence secondary structure
tertiary structure prediction
homology modeling: model unknown sequence onto known structure of homolgous protein
Ab initio prediction: from chemical principles, and statistics of conformations of stretches of amino acids in known structures
e.g Rosetta@home
structural evolution
a common mechanism of protein evolution is duplication of a protein sequence, followed by gradual