Hydrophobic compactnessmolton globule distant

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Hydrophobic (compactness/molton globule, distant neighbor) Folding Pathways Funnels Explore the energy landscape or conformational space (degrees of freedom) Proc. Natl. Acad. Sci . USA 89:8721-8725 (1992)
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Characteristics of Folded State Tight packing – compact Sequence determined/environment modulated – (N-P) Search Space Families and symmetry Each sequence unique structure Native state is thermodynamically stable (lowest energy) USA Dogma
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Computational Modeling Major area of research Infancy We still cannot accurately fold proteins by computer Needed: 1. Understanding process 2. Defining the minimum 3. Faster computers 4. Models testable by experimentation That’s why folding and design are two different formulations of the same problem
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In Vivo Folding Chaperones – bind to incompletely folded polypeptides Prevent aggregation Regulate translocation Foldases – catalyze folding N I U chaperones Native Intermediate Folding Rx’s: -Disulfide Bonds -x-pro peptide bonds -cis-trans isomers Goal: To prevent aggregation (collapsed intermediates) and alternatively folded states
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Why won’t it fold? Most common obstacles to a native fold: • Aggregation • Non-native disulfide bridge formation • Isomerization of proline
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Chaperonins / Heat Shock Proteins HSPs help proteins fold by preventing aggregation Recognize only unfolded proteins Not specific Recognizes exposed HB patches Prevent aggregation of unfolded or misfolded proteins • HSP70 Assembly & disassembly of oligomers Regulate translocation to ER HSP60 (GroEL) & HSP10 (GroES) Work as a complex
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Each subunit Apical (  motif) Opening of chaperone to unfolded protein • Flexible • HB Intermediate ( helices) Allow ATP and ADP diffusion Flexible hinges Equatorial ( helices) ATP binding site Stabilizes double ring structure Central cavity up to 90Å diam. 7 subunits in one ring 2 rings back to back GroEL
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