Glucocerebrosidase Molecular Dynamics Simulation

Introduction

Molecular dynamics simulations (MD) calculate the time dependent behavior of a molecular system and therefore provide detailed information on the fluctuations and conformational changes of proteins. The method is based on Newtons second law of motion and the potential energy is calculated using force fields. Biomolecules are approximated as a physical network of spheres that have point charges at their centers and are connected by springs. Electrons are not explicitly examined (cf. Born-Oppenheimer Approximation). The method was first introduced in 1957 by Alder and Wainwright to study interactions of hard spheres. The first protein simulations were carried out in 1977 by McCammon and Gelin to model BPTI. <ref>http://www.ch.embnet.org/MD_tutorial/pages/MD.Part1.html</ref>

In this task Gromacs was used to perform a Molecular Dynamics Simulation with the wildtype structure 2NT0 of Glucocerebrosidase as well as with two mutated structures. The task description is available here.

Gromacs is a package which simulates the Newtonian equations of motion, so called molecular dynamics, for large systems and was was first developed in Herman Berendsens group, department of Biophysical Chemistry of Groningen University. <ref>http://www.gromacs.org/About_Gromacs</ref>

Selection of the mutations

In addition to the wildtype structure we used two mutated structures for the Molecular Dynamics Simulation. Therefore we decided to take mutation number 7 and 10 as numbered in the previous tasks (6 and 7).

Mutation 7: Asn - Ser (Pos. 409/370)

We chose mutation number seven because it is the most common mutation in Gaucher Disease Type 1. In the sequence based analysis we had problems to clearly classify the mutation as damaging. We hope to get more insight into the damaging effect by molecular dynamics.

Mutation 10: Leu - Pro (Pos. 509/470)

We chose mutation number ten because in the sequence based analysis we predicted it as damaging. Although all our observations led us to this prediction the mutation is not listed in HGMD. So we want to analyse this mutation closer with molecular dynamics.

Workflow

We followed all the steps described here. Therefore we used one chain. Our molecule had no crystal water, so we had not to create a new file with the crystal water. After adding the number of Natrium and Chlorid ions we had to check, if there are clashes with the crystal water. As we had none in our structure there were no clashes and we got REMARK 0 as a result.

For the production run we copied the .mdp, .gro, .top and .tpr files to our LRZ directory. There we created a "molecular dynamics" directory with one directory for each run (wt, mut7 and mut10).

Analysis

The results of the MD runs are presented on the following page: Task 10 - Molecular Dynamics Simulations Analysis