Protein Folding

1
Protein Folding

• A perspective from theory and experiment

Episode 1 Introduction, Folding mechanisms and
pathways, Molecular reaction dynamics
http//www.biochem.oulu.fi/juffer/
2
Introduction (1)

• We know
• Proteins are involved in virtually every process
  (catalysis of chemical reactions, maintenance of
  electrochemical potential across membranes,
  etc.).
• Proteins are synthesized on ribosomes as linear
  chains of amino acids.
• To function, proteins must adopt a native 3D
  structure that is characteristic for each
  protein.
• Folding involves complex molecular recognition
  process that depends on the cooperative action of
  many interactions.
• Folding is an heterogeneous process Net
  stability is the result of an interplay between
  entropic and enthalpic contributions.
• Folding mechanism how can the protein find its
  native structure within a short period (s, min)
  of time Levinthal paradox.

3
Classical folding mechanisms
Fersht, Structure and function in protein
science, Freeman, New York, 1999
4
Introduction (2)

• Classical view protein folding is seen as a
  chemical reaction U?P.
• Understanding of reactions is based upon an
  understanding of role of dominant interactions
  that determine
• Potential energy surface.
• Description of dynamics leading from reactants to
  products.

5
Introduction (3)
Transition state
Potential energy surface

• Energy barrier determines reaction rate
• Reaction coordinate describes reaction e.g.
  distance

Molecular reaction dynamics
6
Introduction (4)

• Can we describe the protein folding as a regular
  chemical reaction?
• Reaction dynamics useful for protein folding?
• Example Reaction of molecular Hydrogen with
  atomic Hydrogen HH2?H2H

7
Simple reaction dynamics (1)
Simple reaction HH2?H2H

• 50 change that reaction will occur
• Energy Reactants Energy Products.
• At non-zero T, H-atom and H2 will not exactly
  follow minimum energy path.

8
Simple reaction dynamics (2)

• In protein folding, reaction path is much less
  defined.
• Folding polypeptide chain moves over a larger
  region of the energy surface during folding
  pathway ?
• Both energy and entropy plays a role.

9
Protein energy landscape
Unfolded
Energy
3N dimensional space
Native state
Folded
coordinates, momenta
10
Simple reaction dynamics (3)
Simple reaction
Protein
Energy landscape is very complex, with many
minima and maximums.
11
Folding versus condensation

• Folding process is more like the condensation of
  atomic clusters.
• Time scale of folding is in the order of ms or
  longer, instead a few fs.
• The number of degrees of freedom for protein
  folding is also much larger than in the case of a
  chemical reaction ? There is no simple reaction
  coordinate.

12
The progress variable (1)
TltTm

• How to relate the total free energy to proteins
  conformation, that is how to monitor the folding
  process
• Radius of gyration Rg
• Number of native contacts Q
• Q0 unfolded state
• Q1 native state

TgtTm
13
The progress variable (2)

• Conformational space is limited.
• Quick collapse to a random state (0.2 lt Q lt
  0.9).
• Configurational entropy is compensated by
  hydrophobic burial.
• Highly cooperative process only states
  Q0.2-0.3 and Q1 are significantly populated.

min
Displayed data is the result of a large number of
different protein molecules results reflect an
avarage.
Lower temperature, slow folding
14
The progress variable (3)

• Energy and entropy surface is very broad ?
  system sample large number of conformation.
• E(Q) is monotone decreasing function.
• Energy surface acts as a funnel

Barrier
Higer temperature, fast folding