Predicting the Effect of SNPs (PKU)

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
• GLN172HIS
• ARG158GLN
• 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

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 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]

Prediction: <figure id="fig:mutationGLUGLY">

Aminoacids in the first mutation

</figure>

2D structure projection of glutamic acid with the pK-values for each group. For a better referability the c-atoms are labeled according to the common nomenclature

2D structure projection of glycine with the pK-values for each group. For a better referability the c-atoms are labeled according to the common nomenclature

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 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]

Prediction <figure id="fig:mutationSERARG">

Aminoacids in the second mutation

</figure>

2D structure projection of Serine with the pK-values for each group. For a better referability the c-atoms are labeled according to the common nomenclature

2D structure projection of Arginine with the pK-values for each group. For a better referability the c-atoms are labeled according to the common nomenclature

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. 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]

Prediction: <figure id="fig:mutationSERARG">

Aminoacids in the third mutation

</figure>

2D structure projection of Arginine with the pK-values for each group. For a better referability the c-atoms are labeled according to the common nomenclature

2D structure projection of Glutamine with the pK-values for each group. For a better referability the c-atoms are labeled according to the common nomenclature

Close-up of the mutated Glutamine at residue 158 in PheOH. The best fitting rotamer was chosen to minimize severe or smaller collisions (red to green discs) with neighboring residues. This rotamer appears in 1.7% of mutations according to the PyMol rotamer database.

Mutated Glutamine at residue 158 in PheOH. The residue is located in a helix region and is statistically less likely in this type of structure than the original arginine.

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 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]

Prediction: <figure id="mutationGLNHIS">

Aminoacids in the fourth mutation

</figure>

2D structure projection of Glutamine with the pK-values for each group. For a better referability the c-atoms are labeled according to the common nomenclature

2D structure projection of Histidine with the pK-values for each group. For a better referability the c-atoms are labeled according to the common nomenclature

Close-up of the mutated histidine at residue 172 in PheOH. The best fitting rotamer was chosen to minimize severe or smaller collisions (red to green discs) with neighboring residues. This rotamer appears in 18.9% of mutations according to the PyMol rotamer database.

Mutated histidine at residue 172 in PheOH. The residue is located in a coil region.

ARG243GLN

From pos. charged, polar, strongly hydrophilic to neutral, polar, strongly hydrophilic.

Close-up of the mutated histidine at residue 243 in PheOH. The best fitting rotamer was chosen to minimize severe or smaller collisions (red to green discs) with neighbouring residues. This rotamer appears in 17.3% of mutations according to the PyMol rotamer database.

Mutated glutamine at residue 243 in PheOH. The residue is located in a sheet region.

LEU255SER

From neutral, non polar, strongly hydrophobic to neutral, polar, slightly hydrophilic.

Close-up of the mutated serine at residue 255 in PheOH. The best fitting rotamer was chosen to minimize severe or smaller collisions (red to green discs) with neighbouring residues. This rotamer appears in 42.9% of mutations according to the PyMol rotamer database.

Mutated serine at residue 255 in PheOH. The residue is located in a helix structure.

MET276VAL

From neutral, non-polar, hydrophobic to neutral, non-polar, strongly hydrophobic.

Close-up of the mutated valine at residue 276 in PheOH. The best fitting rotamer was chosen to minimize severe or smaller collisions (red to green discs) with neighbouring residues. This rotamer appears in 94.5% of mutations according to the PyMol rotamer database.

Mutated valine at residue 276 in PheOH. The residue is located in a coil.

ALA322GLY

From neutral, non-polar, hydrophobic, small to neutral, non-polar, slightly hydrophilic, small.

Close-up of the mutated glycine at residue 322 in PheOH. There is only one rotamer and there can not be collisions with neighbouring residues as glycine is the smallest amino acid.

Mutated glycine at residue 322 in PheOH. The residue is located in a helix region.

GLY337VAL

From neutral, non-polar, slightly hydrophilic, small to neutral, non-polar, strongly hydrophobic, medium sized.

Close-up of the mutated valine at residue 337 in PheOH. The best fitting rotamer was chosen to minimize severe or smaller collisions (red to green discs) with neighbouring residues. This rotamer appears in 2.9% of mutations according to the PyMol rotamer database.

Mutated valine at residue 337 in PheOH. The residue is located in a loop between two sheet elements.

ARG408TRP

From pos. charged, polar, strongly hydrophilic, medium sized to neutral, non-polar, slightly hydrophilic, large.

Close-up of the mutated tryptophan at residue 408 in PheOH. The best fitting rotamer was chosen to minimize severe or smaller collisions (red to green discs) with neighbouring residues. This rotamer appears in 2.3% of mutations according to the PyMol rotamer database.

Mutated tryptophan at residue 408 in PheOH. The residue is located in a coil near a helix region.

References

A helix propensity scale based on experimental studies of peptides and proteins.