Molecular Dynamics Simulations Hemochromatosis

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Hemochromatosis>>Task 8: Molecular dynamics simulations

Short task description

Detailed description: Molecular dynamics simulations

In this task we picked 3 mutations from the previous tasks and performed molecular dynamics simulations for them (using AGroS). The evaluation of these simulations will be part of task 10 though.


A protocol with a description of the data acquisition and other scripts used for this task is available here.


We have chosen R224W and C282S for the molecular dynamics simulations. C282S in order to see the impact of the broken disulfide bridge as well as its similarity to C282Y, one of the most common hemochromatosis mutations. R224W was chosen to further analyse this ambiguous mutation and maybe to finally clarify if it is malign or benign.

Molecular Dynamics Simulation runs:

  • Wildtype (status: finished...)
  • R224W (status: finished...)
  • C282S (status: finished...)

AGroS pipeline and intermediate PDB files

The different steps performed by AGroS:

  • Runs RepairPDB and findBreaks, additional scripts to adapt PDB files to MD reality.
  • Runs STRWater, an additional script that saves information for Structural Water Molecules in PDB file.
  • Runs SCWRL, a program employed to correctly assign side chain information to PDB structures.
  • Runs minimization in vacuum.
  • Creates water box, includes solvent (water with 0.1 [NaCl]) and neutralizes protein intrinsic charge.
  • Creates restrain files for each chain individually.
  • Runs solvent minimization with fixed Protein (backbone + sidechains).
  • Runs minimization with fixed Backbone.
  • Runs minimization with fixed Backbone (CG).
  • Runs short production NVT MD.
  • Runs short production NPT MD.
  • Runs Production MD.

<figure id="preproc">

Figure 1: The different states of 1a6zC's preprocessing for the MD simulation. Intermediate PDB files shown are: 1a6zC.pdb (green), 1a6zC_repair.pdb (blue), 1a6zC_sc.pdb (cyan), 1a6zC_solv.pdb (yellow), 1a6zC_solv_min.pdb (orange), 1a6zC_solv_min2.pdb (red), and 1a6zC_solv_min3.pdb (magenta). All PDB files were filtered for the protein only (repairPDB -jprot).


Intermediate PDB files:

  • 1a6zC.pdb (input structure with clashing water removed)
  • 1a6zC_br.pdb (just the protein to find breaks)
  • 1a6zC_br_0.pdb (same as above, but one file per chain)
  • 1a6zC.pdb2 (hydrogens removed from 1a6zC.pdb)
  • 1a6zC_repair.pdb (DNA removed and renumbered residues)
  • 1a6zC_repair_0.pdb (same as above, but one file per chain)
  • 1a6zC_water.pdb (structural water from 1a6zC.pdb, B-Factor cutoff 15)
  • 1a6zC_dna.pdb (just the DNA from 1a6zC.pdb)
  • 1a6zC_sc.pdb (SCWRL output for 1a6zC_repair.pdb)
  • 1a6zC_nh.pdb (just the protein from 1a6zC_sc.pdb, plus structural water, plus DNA)
  • 1a6zC_solv_tmp.pdb (ions added)
  • 1a6zC_solv.pdb (duplicate water removed)
  • 1a6zC_solv.pdb2 (just the protein, plus DNA)
  • 1a6zC_solv_0.pdb (input to generate restrictions per chain)
  • 1a6zC_solv_min.pdb (minimized solvent with fixed protein)
  • 1a6zC_solv_min.pdb2 (just the protein from 1a6zC_solv_min.pdb)
  • 1a6zC_solv_min_0.pdb (input to generate restrictions per chain)
  • 1a6zC_solv_min2.pdb (minimization with fixed backbone)
  • 1a6zC_solv_min3.pdb (minimization with fixed backbone, with conjugate gradient)

<xr id="preproc"/> shows seven of the intermediate PDB files. These are 1a6zC.pdb (green), 1a6zC_repair.pdb (blue), 1a6zC_sc.pdb (cyan), 1a6zC_solv.pdb (yellow), 1a6zC_solv_min.pdb (orange), 1a6zC_solv_min2.pdb (red), and 1a6zC_solv_min3.pdb (magenta). During the preprocessing stage 1a6zC experiences only minor changes to its structure, such as small shifts to the coiled regions or bending of a helix (in the front of the figure).