Molecular Dynamics Simulations Gaucher Disease

In this task, we carried out molecular dynamics simulations on the LRZ supercomputer which were analysed in the subsequent task. Simulating the the motions of proteins under different conditions can give insights about the functions of proteins and is used to study diseases which are caused by misfolded proteins. Here, we employed molecular dynamics simulations to investigate the impact of two point-mutations in glycosylceramidase.

Input structures

We applied molecular dynamics simulations for three structures of glycosylceramidase: the wildtype 2nt0_A which served as reference and the two mutants W209R and L470P which were generated by FoldX. W209R is a disease-causing mutation which might severely change the protein structure since the site is part of a alpha-helix and the negative arginine is likely to interfere with the hydrophobic environment. L470P is not listed in the HGMD and is therefore not disease-causing. However, both the sequence-based mutation analysis and the structure-based mutation analysis suggested that this mutation might be deleterious. By simulating structural changes caused by this mutations, we hoped to get a better about its impact on the phenotype.

Preparation

The input structures and output files are stored in a repository which can be checked out by:

git clone /mnt/home/student/angermue/mp/tasks/task08

We followed this description for preparing the molecular dynamics simulation:

1. We checked out AGroS from https://github.com/offmarc/AGroS.
2. We downloaded Scwrl4 from http://dunbrack.fccc.edu/scwrl4 and installed it into the same directory as AGroS.
3. We prepared the job scripts.
4. We submitted the scripts via sbatch SCRIPT-FILE on host lxa1 which runs the SLURM scheduler

AGroS is a script for automizing molecular dynamics simulations via GROMACS and performs following steps:

1. Repairing breaks, missing atoms of the input structure.
2. Calling SCWRL for optimizing side chains.
3. Adding water, 0.1 NaCl, and neutralization protein intrinsic charge.
4. Minimization of the solvent.
5. Short NVT (constant moles, volume, temperature) simulation.
6. Short NVP ( constant moles, pressure, temperature) simulation.
7. Long MD simulation.

We called AgroS with the default parameters which resulted in 50 ps long NVT and NVP simulation and a 10 ns long MD simulation.