Question

Describe the likely order of events for the folding of a globular protein and why is this sequence of events likely? What is the chemical/physical rationale for each step? Include a brief discussion of Levinthal’s paradox.

Answer 1

There are two mechanisms for globular protein folding and the two mechanisms are diffusion collision model or nucleation condensation model. Order of events for this globular protein folding are primary, secondary, tertiary, quarternary.

• Sequence of aminoacids are held together by peptid bonds is seen in primary structure
• The folding of protein is initiated in secondary structure and it consists of two types of structures, first one is alpha helix which is a coil shaped structure with hydrogen bonds and second one is beta pleated sheet which is in S shaped pattern with hydrogen bonds.
• In tertiary structure, a 3D structure with ionic interactions, disulphide bridges, hydrophobic interactions, Vanderwaals forces and hydrogen bonds is formed by the folding of globular protein.
• Number and arrangement of multiple folded protein subunits with respect to one another is seen in quarternary structure.

The main driving force behind this folding process is minimising the number of hydrophobic side chains which are exposed to water. The folding process maintains the functional property of the protein.

Physically/chemically, the main factor for protein folding is the thermodynamics of the structure which is the main stabilizing force present within the protein. Next to this , another interaction are also present within protein called hydrophobic interactions for protein folding. Hydrophobic interactions have impact on primary, secondary and tertiary structure. The disulphide bridges are the other interactions present in protein folding.  

Levinthal's paradox provides a self reference for protein folding theory. Paradox refers to the spontaneous folding of protein on millisecond or microsecond time scale. There is astronomical number of possible conformations present in a molecule because of the polypeptide chains have large number of degrees of freedom. So a polypeptide requires a time about longer than age of universe to attain at it's correct naive conformation. Then the Levinthal's paradox refers the descrepncy between this large time estimate and real folding times of protein which are in milliseconds or microseconds time scale.