Difference between revisions of "Predicting the Effect of SNPs (PKU)"

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(GLU76GLY)
(GLU76GLY)
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===GLU76GLY===
 
===GLU76GLY===
As this mutation results in a change from [http://www.biology.arizona.edu/biochemistry/problem_sets/aa/glutamate.html Glutamic acid] to [http://www.biology.arizona.edu/biochemistry/problem_sets/aa/Glycine.html 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 to ions, which play a major role in PheOH-activity.
+
As this mutation results in a change from [http://www.biology.arizona.edu/biochemistry/problem_sets/aa/glutamate.html Glutamic acid] to [http://www.biology.arizona.edu/biochemistry/problem_sets/aa/Glycine.html 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'']
 
*Keychanges: [From ''negativly charged, polar, strongly hydrophilic, medium sized'' '''to''' ''neutral, non-polar, non-hydrophilic, small'']
  +
Prediction:[[File:approved.jpg|100px|]]
 
<figure id="fig:mutationGLUGLY">
 
<figure id="fig:mutationGLUGLY">
 
<center><small><caption>Aminoacids in the first mutation</caption></small></center>
 
<center><small><caption>Aminoacids in the first mutation</caption></small></center>

Revision as of 13:41, 14 June 2012

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:Approved.jpg <figure id="fig:mutationGLUGLY">

Aminoacids in the first mutation

</figure>

2D structure projection of Glutamicacid 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 Glycinewith 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.

  • Keychanges [From neutral, polar, slightly hydrophilic to pos. charged, polar, strongly hydrophilic]

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

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 neighbouring 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

From neutral, polar, strongly hydrophilic to neutral, polar, strongly hydrophilic, ring-structure


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 neighbouring 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 region.

MET276VAL

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

Close-up of the mutated XXXX 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 XXX% of mutations according to the PyMol rotamer database.
Mutated XXX at residue 276 in PheOH. The residue is located in a XXX region.

ALA322GLY

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

Close-up of the mutated XXXX at residue 322 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 XXX% of mutations according to the PyMol rotamer database.
Mutated XXX at residue 322 in PheOH. The residue is located in a XXX region.

GLY337VAL

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

Close-up of the mutated XXXX 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 XXX% of mutations according to the PyMol rotamer database.
Mutated XXX at residue 337 in PheOH. The residue is located in a XXX region.

ARG408TRP

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

Close-up of the mutated XXXX 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 XXX% of mutations according to the PyMol rotamer database.
Mutated XXX at residue 408 in PheOH. The residue is located in a XXX region.

References

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