WHY do hemoglobin molecules polymerize?

In this animated graphic, 2 molecules of sickle hemoglobin (HbS) are shown sticking together.  They stick together because the sixth amino acid of the b-chains (blue)  in HbS is Valine (green) instead of the normal Glutamic Acid.
 

The hydrophobic Valine side chain is exposed on the surface of the two b-chains of HbS and can fit into hydrophobic pockets created by the side chains of Phenylalanine (amino acid 85) and Leucine (amino acid 88) also on the b-chain surface.  When HbS is oxygenated, the alpha helix of which valine is a part is "hinged" in position so that the valine does not reach the hydrophobic pocket.  However when HbS loses its oxygen as it travels through the capillaries, the alpha helix "hinges" at a different angle, which places the 6th valine in a position where it can fit into the hydrophobic pocket. The position of amino acids 6, 85 and 88 can be seen in this drawing  of a b globin chain  (from Strickberger, MW.  Genetics, 3rd ed., Macmillan, 1985.  p 540). This does not occur in the wild type b globin because glutamic acid has a very hydrophilic R group!     On the b globin graphic, find amino acids 6, 85 and 88 !

 
 
 

1. Images from: http://bioweb.ncsa.uiuc.edu/educwb/index2.html	2.
	3.

Image 1.    Transmission electron micrograph (TEM) of a sickled cell showing fibers.  Some of the fibers are outside of the erythrocyte.  Each fiber is composed as follows:

Image 2.    Model of a single fiber of polymerized HbS molecules as shown in (1).  The fibers in (1) are actually composed of 7 double stranded fibers twisted together - one of the double stranded fibers is shown in white.

In this image each ball represents an individual HbS tetramer.  The HbS molecules are stuck together, as explained above, so that they form the double stranded fibers which then twist together to form a larger strand of 7 double strands.

Image 3.    Cross section of the large fiber in (2).  The red lines show the HbS tetramers which are paired in each of the 7 double stranded fibers.  Remember that each HbS tetramer is composed of 2 a chains (yellow) and 2 b chains (white).  In this image the balls represent individual atoms.
 
 

NOTE:  There are many levels of structure in the case of sickled hemoglobin Amino Acid Sequence  -->  a Helix  -->   a globin -->  HbS tetramer -->  double stranded fiber --> 7 double stranded fibers                                            random coil    b globin                                                                             twisted into large fiber

Primary                      Secondary        Tertiary        Quaternary            5th level                          6th level Structure                    Structure         Structure       Structure

 

BOTTOM LINE:      A  very small change  in the Primary Structure of a protein may result in severe phenotypic effects!  This is particularly true if the R group of the amino acid in the wild type protein is replaced by an amino acid whose R group has very different chemical properties (size, shape, solubility, charge).