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Lectures 6 7 -Protein_Folding

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 NI 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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• Cap to the GroEL • Each subunit sheet hairpin (roof) – Mobile loop (int w/ GroEL) • 7 subunits in functional molecule GroES
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GroEL+ GroES work together • GroEL makes up a cylinder – Each side has 7 identical subunits
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