Difference between revisions of "Predicting the Effect of SNPs (PKU)"
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== Investigated SNPS == |
== Investigated SNPS == |
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+ | In the following section, we present the information we gathered for each SNP individually. Summary comments on the methods we used, we placed at subsites. These include the |
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+ | [[PsiBlast in Big80 (PKU)|PsiBlast Profile]] of our protein, [[PsiPred of Mutated PAH|PsiPred Predictions]] of the mutated sequences, the complete [[Multiple Alignment Mammalian PheOH|Alignment of 22 mammalian homologs to PAH]] and the [[SNP effect predictions (PKU)|SIFT, PolyPhen and SNAP predictions]]. |
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− | ===Stuff We Should Mention Somewhere=== |
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− | [[PsiBlast in Big80 (PKU)|PsiBlast Profile]] |
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− | [[PsiPred of Mutated PAH|PsiPred Predictions]] |
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− | [[Multiple Alignment Mammalian PheOH|Alignment of 22 mammalian homologs to PAH]] |
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===GLU76GLY=== |
===GLU76GLY=== |
Revision as of 13:13, 16 June 2012
Contents
Short Introduction
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.
Our dataset
we propose the following dataset:
- GLU76GLY
- SER87ARG
- ARG158GLN
- GLN172HIS
- ARG243GLN
- LEU255SER
- MET276VAL
- ALA322GLY
- GLY337VAL
- ARG408TRP
You could check them, if you like.. I put them together 5 minutes ago and already forgot, which are which. ;-)
Investigated SNPS
In the following section, we present the information we gathered for each SNP individually. Summary comments on the methods we used, we placed at subsites. These include the PsiBlast Profile of our protein, PsiPred Predictions of the mutated sequences, the complete Alignment of 22 mammalian homologs to PAH and the SIFT, PolyPhen and SNAP predictions.
GLU76GLY
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 could be 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.We do not have any structural data for this point, but predictions suggest a position either in a helix or at the edge of a sheet structure. 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 with respect to the strong affinity of glutamic acid to ions, which plays a major role in PheOH-activity.
- Keychanges: [From negativly charged, polar, strongly hydrophilic, medium sized to neutral, non-polar, non-hydrophilic, small]
- BLOSUM62/PAM250/PAM1: -2(-4,+6)/9 (0,12)/4 (0,9865)
- SIFT: TOLERATED with a score of 0.18.
- PolyPhen (HumVar): BENIGN 0.007 (sensitivity: 0.97; specificity: 0.46)
Prediction:
<figure id="fig:mutationGLUGLY">
</figure>
SER87ARG
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 amino acid. 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"/>). It is predicted to be two positions N-terminal of a helix structure. 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 used amino acid (mostly appearing in the catalytic domain for phosphorylated substrates), we would say, that this is rather a disease causing mutation.
- Keychanges: [From neutral, polar, slightly hydrophilic to pos. charged, polar, strongly hydrophilic]
- BLOSUM62/PAM250/PAM1: 1(-3,+4)/11 (1,10(sic!))/6 (1,9840)
- SIFT: TOLERATED with a score of 0.54.
- PolyPhen (HumVar): BENIGN 0.094 (sensitivity: 0.91; specificity: 0.68)
Prediction
<figure id="fig:mutationSERARG">
</figure>
ARG158GLN
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.
- Keychanges: [From pos. charged, polar, strongly hydrophilic to neutral, polar, strongly hydrophilic]
- BLOSUM62/PAM250/PAM1: 1(-3,+5)/5 (1,17)/9 (0,9913)
- SIFT: AFFECT PROTEIN FUNCTION with a score of 0.00.
- PolyPhen (HumVar): PROBABLY DAMAGING 1.000 (sensitivity: 0.00; specificity: 1.00)
Prediction:
<figure id="fig:mutationSERARG">
</figure>
GLN172HIS
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 amino acid 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]
- BLOSUM62/PAM250/PAM1: 0(-3,+5)/7 (0,10)/23 (0,9876)
- SIFT: AFFECT PROTEIN FUNCTION with a score of 0.03.
- PolyPhen (HumVar): BENIGN 0.170 (sensitivity: 0.89; specificity: 0.72)
Prediction:
<figure id="mutationGLNHIS">
</figure>
ARG243GLN
From pos. charged, polar, strongly hydrophilic to neutral, polar, strongly hydrophilic.
- BLOSUM62/PAM250/PAM1: 1(-3,+5)/5 (1,17)/9 (0,9913)
- SIFT: AFFECT PROTEIN FUNCTION with a score of 0.00.
- PolyPhen (HumVar): PROBABLY DAMAGING 1.000 (sensitivity: 0.00; specificity: 1.00)
LEU255SER
From neutral, non polar, strongly hydrophobic to neutral, polar, slightly hydrophilic.
- BLOSUM62/PAM250/PAM1: -2(-4,+4)/4 (1,34)
- SIFT: AFFECT PROTEIN FUNCTION with a score of 0.00.
- PolyPhen (HumVar): PROBABLY DAMAGING 1.000 (sensitivity: 0.00; specificity: 1.00)
MET276VAL
From neutral, non-polar, hydrophobic to neutral, non-polar, strongly hydrophobic.
- BLOSUM62/PAM250/PAM1: 1(-3,+5)/2 (0,6)/4 (0,9874)
- SIFT: TOLERATED with a score of 0.06.
- PolyPhen (HumVar): BENIGN 0.081 (sensitivity: 0.92; specificity: 0.67)
ALA322GLY
From neutral, non-polar, hydrophobic, small to neutral, non-polar, slightly hydrophilic, small.
- BLOSUM62/PAM250/PAM1: 0(-3,+4)/12 (2,13)/21 (0,9876)
- SIFT: AFFECT PROTEIN FUNCTION with a score of 0.01.
- PolyPhen (HumVar): POSSIBLY DAMAGING 0.707 (sensitivity: 0.78; specificity: 0.85)
GLY337VAL
From neutral, non-polar, slightly hydrophilic, small to neutral, non-polar, strongly hydrophobic, medium sized.
- BLOSUM62/PAM250/PAM1: -3(-4,+6)/4 (0,27)/5 (0,9935)
- SIFT: AFFECT PROTEIN FUNCTION with a score of 0.00.
- PolyPhen (HumVar): POSSIBLY DAMAGING 0.597 (sensitivity: 0.81; specificity: 0.83)
ARG408TRP
From pos. charged, polar, strongly hydrophilic, medium sized to neutral, non-polar, slightly hydrophilic, large.
- BLOSUM62/PAM250/PAM1: -3(-3,+5)/2 (1,17)/ 2 (0, 9913)
- SIFT: AFFECT PROTEIN FUNCTION with a score of 0.00.
- PolyPhen (HumVar): PROBABLY DAMAGING 0.999 (sensitivity: 0.09; specificity: 0.99)
References
A helix propensity scale based on experimental studies of peptides and proteins.