Predicting the Effect of SNPs (PKU)
This week's task builds on the data gathered last week. We blindly choose 5 disease causing and 5 harmless SNPs and will try to predict their effect from the sequence change alone. You may find a detailed task description at the usual place and consult our task journal.
we propose the following dataset:
You could check them, if you like.. I put them together 5 minutes ago and already forgot, which are which. ;-)
As this mutation results in a change from Glutamic acid to Glycine which have some differences in structure as can bee seen in <xr id="fig:mutationGLUGLY"/> we expect this change to be of rather minor effect. Of course Glutamic acid is charged under biological conditions and Glycine is not, but Glycine is kind of a universal substitution, because it is neither hydrophobic nor hydrophilic. Additionally, as it is the smallest amino acid, it can not produce any sterical problems. Of course it might be that the Glycine can not stabilize any structure, which should be present at this residue, but as we do not have any structural data for this point we only can rely on the physiochemical properties, for which we would say, that these changes are not drastic enough to cause the disease. If the mutation would have occurred rather near the catalytic site, our judgment would have been different as for the strong affinity, of Glutamic acid, to ions, which play a major role in PheOH-activity
- Keychanges: [From negativly charged, polar, strongly hydrophilic, medium sized to neutral, non-polar, non-hydrophilic, small]
we expect that this mutation, which causes a change from Serine to Arginine, has a bigger effect on the protein, than the one above. With this mutation the strength of the effect depends completely on the location of the aminoacid. Both of the amino acids are hydrophilic, but as Arginine is one of the snorkeling, because of its rather hydrophobic stem, the changes can be rather serious(<xr id="fig:mutationSERARG"/>). As the overall change of size and the change in polarity from rather negative to positive and regarding the fact, that arginine is a rather seldom (mostly in the catalytic domain for phosphorylated substrates )used amino acid, we would say, that this is rather a disease causing mutation.
- Keychanges: [From neutral, polar, slightly hydrophilic to pos. charged, polar, strongly hydrophilic]
From the secondary structure of both amino acids (<xr id="fig:mutationSERARG"/> left side), one would guess, that if an Arginine fits in this region, a Glutamine will fit there as well. But if one looks at the right side of this figure, in the close-up there are some small red discs, which indicate sterical collisions. These are due to the additional hydroxl-group, where the original amino acid only had hydrogen-atoms. Depending on the importance of this site and the collision's this mutation can have almost no or a very big effect. But since the sidechain collides in the inside of the protein, we would predict a rather serious effect. This idea is getting supported by the information from the PyMol database that this changes is not observed very often, in spite of the rather similar structure of the two amino acids.
- Keychanges: [From pos. charged, polar, strongly hydrophilic to neutral, polar, strongly hydrophilic]
This mutation is rather easy on the first sight. The general chemical properties are the same. The aminoacids only differ in size and structure. As one can see in <xr id="mutationGLNHIS"/> on the right, there are some collisions with the structure. BUt due to the fact, that this aminoacid is located on the outside of the protein and also located in a coiled region which only interferes with another coiled region, we are quite sure, that this mutation is not disease causing.
- Keychanges: [From neutral, polar, strongly hydrophilic to neutral, polar, strongly hydrophilic, ring-structure]
From pos. charged, polar, strongly hydrophilic to neutral, polar, strongly hydrophilic.
From neutral, non polar, strongly hydrophobic to neutral, polar, slightly hydrophilic.
From neutral, non-polar, hydrophobic to neutral, non-polar, strongly hydrophobic.
From neutral, non-polar, hydrophobic, small to neutral, non-polar, slightly hydrophilic, small.
From neutral, non-polar, slightly hydrophilic, small to neutral, non-polar, strongly hydrophobic, medium sized.
From pos. charged, polar, strongly hydrophilic, medium sized to neutral, non-polar, slightly hydrophilic, large.
A helix propensity scale based on experimental studies of peptides and proteins.