Protein Folding in a Curved Space
The diagram shows the main stages of protein folding, and as a good introduction to help me understand the article posted below, I've added here the description that went with the diagram:
Protein folding is the transaction by which an unfolded polypeptide chain folds into a specific native and functional structure. After leaving the ribosome, the polypeptide chain goes through a number of steps, the folding pathway, ‘ in which the protein has to go through a sequence of intermediates to fold into the native structure’ (Arai M, Kuwajima K 2000). Recent studies (Arai M, Kuwajima et al, 2000) using data and propositions from both experimental (Ptitsyn 1995, Kuwajima 1992,1996, Baldwin 1995,1996,1999) and theoretical studies (the ‘energy landscape’ theory as proposed by Dill and Chan,1997 and Nyemeyer et al, 1998) have suggested that protein folding is divided into two stages.
The first stage involves the formation of the molten globule state from the unfolded polypeptide chain; a flexible intermediate where the protein forms its basic structural framework but with no specific side-chain packing. The second stage involves the formation of the native state from the molten globule state; specific tertiary structure is assembled with precise hydrophobic interactions and side-chain packing. This subsequent folding often requires specific molecules called molecular chaperones to help in the formation of the precise native state. More recent studies have however indicated that these two steps may not be as distinct from one another as previously thought, and some now feel that co-translational protein folding is a more accurate model.
Once individual proteins are folded correctly it is possible for multiprotein complexes to form, which may be an essential step in forming the protein’s quaternary structure. Multiprotein complex formation is an all-or-nothing process to insure that efficient functional complexes are formed without the hindrance that can be caused by incomplete assembly. Linkage plays an important role in insuring all-or-none assembly. If proteins misfold then systems to cope with this exist within the cell. The unfolded protein response deals with an accumulation of misfolded proteins in the ER, providing a route for misfolded proteins to retry folding. If the protein is irretrievable by this process then they are degraded by ubiquitin-dependent proteolytic degradation.
And we go merrily along, unaware of all this fabulous activity taking place at lightning speed inside us that keeps us alive!
Physics news Update 803
Protein Folding in a Curved Space
Physicists at the Università di Firenze, in Italy, have put a new slant on the protein folding problem. Proteins are special polymers made of amino acids. Generic polymers, when you cool them enough, will collapse in a ball. Proteins do something more interesting: they fold up into a particular compact form. If a protein fails to find this form it won't be able to carry out its designated function and disease can result. For instance, some nonfolding proteins will aggregate into long filaments, amyloid fibrils, and this has proven to be the basis for neurodegenerative diseases like Alzheimer's.
Finding the precise dynamics behind protein folding would be like Isaac Newton finding the laws of universal gravitation. We aren't at that point yet, but there are ways of investigating some of the steps proteins take to arrive at their proper form. One fruitful approach is to see the multi-step process as taking place in a series of energy transactions. At any moment the protein can be represented as a point moving around in an abstract space whose coordinates correspond to all possible configurations and the associated energy needed to have that structure, sort of like a ball rolling along on the inner surface of a bowl. The bowl might have some partitions, and the ball might be able to roll up out of one compartment and into a neighboring one if its energy is sufficient, or if the wall between compartments is low enough, or if some extra energy (maybe in the form of heat or a chemical reaction) is added.
Lapo Casetti (firstname.lastname@example.org) and Lorenzo Mazzoni have attempted to make the "energy landscape" method even more geometrical by characterizing the folding forces at work as being a form of curvature in the bowl-like well in which the protein is operating. This is analogous to what Albert Einstein did in characterizing gravity as the curvature of spacetime in which planets and stars move about. Mazzoni and Casetti seek to determine what it is about the curvature of the energy landscape that encourages proteins to fold and other polymers not to fold.