Fabry:Molecular Dynamics Simulations

Fabry Disease » Molecular Dynamics Simulations

---

The following analyses were performed on the basis of the α-Galactosidase A sequence. Please consult the journal for the commands used to generate the results.

Preparation

<figtable id="tab:MutSCWRL"> Mutagenesis of the 2 selected SNPs performed with SCWRL in Task 8. This was done on the basis of a backbone dependant library. The wildtype amino acid is shown in green, the mutated one in red. The whole structure of the wildtype is colored light blue, the mutant light red. Hydrogen bonds of the mutant to the surrounding are depicted in red, those of the not mutated site in green.

R118H

R356W

</figtable>

We chose to use the SNPs R118H and R356W. For the first one we want to examine if it is really not disease causing, although all results indicate otherwise so far. The second one has a strong effect on the protein. For both, we used the structur obtained by Scwrl in Task 8

Intermediate PDB files

<figtable id="tab:files"> The following files were obtained from a short test run with the wild type structure 3S5Y. The chain itself is shown in pink, everything else in blue.

file name	properties	picture
3S5Y_chainA_repaired.pdb	Repaired pdb file (repairPDB applied) of structure 3S5Y as we used it in Task 7
3S5Y_chainA_repaired_repair.pdb 3S5Y_chainA_repaired_repair_0.pdb	Repaired pdb file for structure 3S5Y, for this step the script repairPDB is used to remove potentially included DNA and to change the indices in the pdb file. This is done also for each chain separately, but since we decided to simulate only one chain, there is only one additional file "_0"
3S5Y_chainA_repaired_br.pdb 3S5Y_chainA_repaired_br_0.pdb	Structure 3S5Y, removed ligands and water. Now only the protein itself is included. The applied script finds potential breaks in the structure and divides it into parts. Since our used structure does not have any breaks, there is only one structure and both files are equal.
3S5Y_chainA_repaired_dna.pdb	Contains potential included water less than 15 angstrom away from the structure, that is removed from original structure file in the repair step.	--
3S5Y_chainA_repaired_dna.pdb	Contains potential included DNA, that is removed from original structure file in the repair step.	--
3S5Y_chainA_repaired_sc.pdb	SCWRL applied to the structure. Although we used the SCWRL output file from last week's task there were some changes in the secondary structure. One example can be seen in the lower picture. The original structure is shown in pink, the SCWRL changed one in green.
	Although we used the SCWRL output file from last week's task there were some changes in the secondary structure. One example can be seen on the right. The original structure is shown in pink, the SCWRL changed one in green.
3S5Y_chainA_repaired_nh.pdb	No hydrogens; extracts the protein itself from the SCWRL structure.
Summary of all pdb files	Again, all chain structures, except for one are shown in pink. The green structure is the SCWRL modified one, which differs in some structural aspects from the others. Hetero atoms are shown in blue, those that differ are shown in red. Here we can see, that the repair step deleted the ligand (2R,3S,4R,5S)-2-(hydroxymethyl)piperidine- 3,4,5-triol.
file name	properties	picture
3S5Y_chainA_repaired.pdb	Original pdb file of structure 3S5Y, after applying repairPDB to it

</figtable>

<figure id="fig:Trajectory">

Trajectory of the first 17 states of the wildtype - test call on partition mpp1_inter

</figure>