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Protein Folding: The Sickle Cell Substitution
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<font face="Verdana, Arial, Helvetica, sans-serif" color="#FFFFFF" size="5"><strong>Protein
Folding: </strong>The Sickle Cell Substitution</font>
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<map name="val6andpockets">
<area href="script:jmol:1:select *; wireframe off; restrict protein; select protein; cpk off; wireframe off; trace on; color chain;select ((*B,*D,*F,*H)&62-95); wireframe .15; cpk 20%; trace off; color white; select val6; wireframe .15; cpk 20%; color violet; halos on; color halos violet; moveTo 1 435 -883 -175 166.0 98;" coords="0,0,20,20" shape="rect"></area>
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<map name="stickingsite">
<area href="script:jmol:1:moveTo 1 470 -878 -92 177.8 241; select *H&val6,*B&62-95; color violet; delay .2; color white; delay .2; color violet; delay .2; color violet; select *B&62-95; color chain;" coords="0,0,20,20" shape="rect"></area>
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<map name="val6">
<area href="script:jmol:1:select val6; wireframe .15; cpk 20%; color violet; halos on; delay .2; color white; halos off; delay .2; color violet; halos on; delay .2; color white; halos off; delay .2; color violet; halos on;" coords="0,0,20,20" shape="rect"></area>
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<area href="script:jmol:1:select *H&val6,*B&62-95; restrict selected; moveTo 1 292 -792 -536 101.1 376;" coords="0,0,20,20" shape="rect"></area>
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<map name="hydrophobicity">
<area href="script:jmol:1:select gly or ala or val or leu or ile or phe or pro or trp or met or cys or tyr; color [246, 209, 061]; select asn or gln or ser or thr; color [072, 181, 106]; select asp or glu; color [230, 084, 071]; select lys or arg or his; color [080, 161, 218]; select (*H&val6);color [246, 209, 061]; color halos [246, 209, 061];" coords="0,0,20,20" shape="rect"></area>
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<map name="ballandstick">
<area href="script:jmol:1:select *H&val6,*B&62-95; color chain; trace off; wireframe .15; cpk 20%;select (*H&val6);color violet;" coords="0,0,20,20" shape="rect"></area>
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Here you can see two mutant sickle cell hemoglobin (HbS) molecules.
They're sticking to each other. We'll look closely to see why.
<table border="0">
<tr>
<td width="50" valign="top">
1. <img src="button.gif" usemap="#start">
</td>
<td valign="top">
<font color="green">Start</font><font face="Verdana, Arial, Helvetica, sans-serif" size="3"><br></font>
Here you see a trace of the carbon backbone of each chain, as
before. There are two identical HbS molecules. The one on the left
we will call HbS #1. Its beta chains are red and blue. The one on
the right will be HbS #2, with beta chains green and yellow.
</td>
</tr>
<tr>
<td width="50" valign="top">
2. <img src="button.gif" usemap="#val6">
</td>
<td valign="top">
<font color="green">Show Beta 6 Valines</font><font face="Verdana, Arial, Helvetica, sans-serif" size="3"><br></font>
The amino acids that flash in violet when you press the button are
the ones changed by the sickle cell mutation. These are the beta 6
valines: the sixth amino acid on each beta chain, which the
substitution has changed from a glutamic acid to a valine. To see
each one, zoom in (hold down shift and drag) and rotate (drag).
</td>
</tr>
<tr>
<td width="50" valign="top">
3. <img src="button.gif" usemap="#stickingsite">
</td>
<td valign="top">
<font color="green">Zoom to Hydrophobic pocket</font><font face="Verdana, Arial, Helvetica, sans-serif" size="3"><br></font>
Here we zoom in to the site where HbS #1 and HbS #2 stick together.
</td>
</tr>
<tr>
<td width="50" valign="top">
4. <img src="button.gif" usemap="#restricttostickingsite">
</td>
<td valign="top">
<font color="green">Show only Hydrophobic pocket</font><font face="Verdana, Arial, Helvetica, sans-serif" size="3"><br></font>
Here we cut things away, so you only see what you need to: the
valine belonging to HbS #1, and a part of a beta chain in HbS #2
called the hydrophobic pocket. These two things stick together.
We'll soon see why.
</td>
</tr>
<tr>
<td width="50" valign="top">
5. <img src="button.gif" usemap="#ballandstick">
</td>
<td valign="top">
<font color="green">Hydrophobic pocket in ball and stick mode</font><font face="Verdana, Arial, Helvetica, sans-serif" size="3"><br></font>
Here you can see all the atoms making up the amino acids in the
hydrophobic pocket.
</td>
</tr>
<tr>
<td width="50" valign="top">
6. <img src="button.gif" usemap="#hydrophobicity">
</td>
<td valign="top">
<font color="green">Color by Hydrophobicity</font><font face="Verdana, Arial, Helvetica, sans-serif" size="3"><br></font>
Here the amino acids are colored by their hydrophobicity. Yellow
ones are hydrophobic and the other colors are hydrophilic. The
valine (with halos around its atoms) is also hydrophobic. Rotate the
molecule until you can see how the valine is sticking into a pocket
of mostly hydrophobic amino acids. The glutamic acid in Hb is
hydrophilic, but the valine in HbS is hydrophobic, so it sticks to
the hydrophobic pocket. In the watery environment of the red blood
cell, the two hydrophobic regions on the surface of HbS make the
molecules stick to each other.
</td>
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<tr>
<td width="50" valign="top">
7. <img src="button.gif" usemap="#val6andpockets">
</td>
<td valign="top">
<font color="green">Zooming out</font><font face="Verdana, Arial, Helvetica, sans-serif" size="3"><br></font>
Here the beta 6 valines are shown in violet and the hydrophobic
pockets on the beta chains are shown in white.
</td>
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</table>
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  <font color="green">Reset position</font>
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<font size="4" face="Verdana, Arial, Helvetica, sans-serif">You've seen
two Hbs molecules stuck to each other. Imagine a third one randomly
bouncing up to them. How could it get stuck on? </font>
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<img src="hemoglobinFibers.jpg">
<center>
<b>HbS fibers</b>
</center>
</td>
<td>
<font face="Verdana, Arial, Helvetica, sans-serif">You just saw how
two HbS molecules can stick together. When thousands of HbS
molecules stick together they form fibers. In the picture on the
left, arrows point to these fibers bursting out of a red blood cell.
These fibers distort the shape of the entire blood cell, changing it
from round and flexible to "sickle" shaped and stiff, as in the
picture on the right. Sickled cells can cause blockages in blood
vessels, so that not enough oxygen gets to the tissues. This is a
major cause of the symptoms of sickle cell anemia.</font>
</td>
<td>
<center>
<img src="sickledCell.jpg">
<br>
<b>Three normal red blood cells and one sickled cell</b>
</center>
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</table>
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<font size="4" face="Verdana, Arial, Helvetica, sans-serif">Describe how a
single amino acid substitution causes hemoglobin molecules to stick
together. Use what you know about the structure of Hb and HbS, the
properties of glutamic acid and valine, and how hydrophobicity causes
molecules to behave in water.</font>
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DNA to Proteins and Protein Folding
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