1. Protein Folding

2. PROTEIN FOLDING
• Process in which a polypeptide chain goes from a linear chain of amino acids with vast number of more or less random conformations in solution to the native, folded tertiary (and for multichain proteins, quaternary) structure

3. Protein Folding
Protein folding considers the question of how the process of protein folding occurs, i. e. unfolded  native state.
This very challenging problem has been described as the second half of the genetic code, and as the three-dimensional code, as opposed to the one-dimensional code involved in nucleotide/amino acid sequence.
Importance:
Predict 3D structure from primary sequence
Avoid misfolding related to human diseases
Design proteins with novel functions

4. Why do proteins fold?
In order to carry out their function (for instance as enzymes or antibodies), proteins must take on a particular shape, also known as a "fold." Thus, proteins are truly amazing machines: before they do their work, they assemble themselves! This self-assembly is called "folding."
Forms determines function
Suppose you have some molten iron. You may turn it into nails, hammers, wrenches, etc. What makes these tools different from each other is their form (i.e. their shape and structure).

5. PRIMARY STRUCTURE DETERMINES TERTIARY (AND
QUATERNARY) STRUCTURES.
– demonstrated by the fact that many proteins can refold from a more or less "random coil" set of conformations without "instructions" from any other cellular components
– All the information for 3-dimensional structure is provided by the amino acid sequence.
Proteins fold on a defined pathway (or a small number of alternative pathways); they don't randomly search all possible conformations until they arrive at the most stable (lowest free energy) structure.

6. Anfinsen Experiment
Denaturation of ribonuclease A (4 disulfide bonds), with 8 M Urea containing b- mercaptoethanol, leads to random coil and no activity

7. Anfinsen Experiment
After renaturation, the refolded protein has native activity, despite 105 ways to renature the protein.
Conclusion: All the information necessary for folding into its native structure is contained in the amino acid sequence of the protein.

8. How do proteins fold?
Proteins have primary structures, which is their sequence of amino acids, and secondary structures, which is the three dimensional shape that one or more stretches of amino acids take. The most common shapes are the alpha helix and the beta conformation.
Proteins fold, amazingly quickly: some as fast as a millionth of a second (microsecond)
The normal protein is called PrPC (for cellular). Its secondary structure is dominated by alpha helices.

9. Interactions between the side chains of amino acids determine how a long polypeptide chain folds into the intricate three-dimensional shape of the functional protein. Protein folding, which occurs within the cell in seconds to minutes, employs a shortcut through the maze of all folding possibilities. As a peptide folds, its amino acid side chains are attracted and repulsed according to their chemical proper-ties. For example, positively and negatively charged side chains attract each other. Conversely, similarly charged side chains repel each other. In addition, interactions involving hydrogen bonds, hydrophobic interactions, and disulfide bonds all exert an influence on the folding process. This process of trial and error tests many, but not all, possible configurations, seeking a compromise in which attractions outweigh repulsions. This results in a correctly folded pro­tein with a low-energy state

10. CHAPERONES
It is generally accepted that the information needed for correct protein folding is contained in the primary structure of the polypeptide. Given that premise, it is difficult to explain why most proteins when denatured do not resume their native conformations under favorable environmental conditions. One answer to this problem is that a protein begins to fold in stages during its synthesis, rather than waiting for synthesis of the entire chain to be totally completed. This limits competing folding configurations made available by longer stretches of nascent peptide. In addition, a specialized group of proteins, named “chaperones,” are required for the proper folding of many species of proteins.

11. HSPs in protein folding
The chaperones—also known as “heat shock” proteins—interact with the polypeptide at various stages during the folding process. Some chaperones are important in keeping the protein unfolded until its synthesis is finished, or act as catalysts by increasing the rates of the final stages in the folding process. Others protect proteins as they fold so that their vulnerable, exposed regions do not become tangled in unproductive interactions
The diagram shows the role of heat-shock proteins and a chaperonin in protein folding.  As the ribosome moves along the molecule of messenger RNA, a chain of amino acids is built up to form a new protein molecule.  The chain is protected against unwanted interactions with other cytoplasmic molecules by heat-shock proteins and a chaperonin molecule until it has successfully completed its folding.