Protein Folding

1
Protein Folding

• A perspective from theory and experiment

Episode 2 Experiment, Simulation, Final
conclusions.
http//www.biochem.oulu.fi/juffer/
2
Experimental evidence (1)
Measure for secondary structure
Indication of non-native contacts
Measure for tertiary structure
3
Experimental evidence (2)
Blocked alanine tetrapeptide
4
?-heptapeptide (1)
Each cluster contain a central structure.
Path between clusters of structures at 340 K.
5
?-heptapeptide (2)
Example folding pathways at 340 K. Transition
rates (ns-1) between consecutive clusters are
indicated.
6
Folding scenario (1)

• When polypeptide is placed in refolding
  conditions
• Van der Waals, electrostatic interactions,
  H-bonds, in protein and with solvent stabilizes
  native state Thermodynamic stability.
• The greater stability of native state does not
  explain why the protein finds the native state.
• Essential element Search is not random, but
  restricted
• Certain parts of energy landscape are of such
  high energy that protein will not sample these
  parts.
• Bias towards native state.
• There is no Levinthal paradox.

7
Folding scenario (2)

• One scenario polypeptide chain collapses rapidly
  to a compact globule
• Due to burial of hydrophobic groups
• Globule has relative high configurational entropy
  if contacts between residues are non-specific,
  or,
• Globule has specific contacts with relative low
  configurational entropy.
• Small (lt100 residues) proteins continuous
  decrease of free energy.
• Larger proteins more complex intermediate states

8
The folding funnel
Increase of progress variable
Decrease of free energy
Fast folding of a 60 residue protein
9
Unified view of protein folding (1)

• Folding is a progression in which many nonnative
  and native contacts stabilizes native like
  features of the structure.
• Energy penalty of nonnative interactions, or
  misfolding, increases throughout the folding
  process.
• For an effective search, protein is directed to
  productive regions of space by stabilizing
  interactions.
• Continuous funnel seems unlikely
• Step-wise behavior, involving sampling of regions
  that are downhill or even uphill appears more
  probable.
• Trajectory of individual protein molecules are
  very different.
• The ensemble of individual molecule trajectories
  samples configuration space.

10
Unified view of protein folding (2)

• How is this all encoded in the sequence?
• Sequence determines energy landscape.
• Specific nature of the residues becomes more and
  more important as the protein approaches native
  state.
• Local interactions lead to significant
  probability of formation of native helices and
  sheets.