Usage

PyRod analyzes the protein environment of water molecules in molecular dynamics simulations to characterize the binding pocket of proteins. An extensive review on the importance of water molecules in ligand binding can be found here.

Input Data

MD simulations can be generated with your favorite MD simulation package. PyRod supports the four major force fields OPLS, GROMACS, AMBER and CHARMM. Also the water model is up to you. Using replicas is strongly recommended (importance of replicas paper). After simulation you need to prepare the MD simulation, i.e. centering the protein in the water box and aligning the protein. VMD allows for both by first running the following command in the Tk console:

pbc wrap -centersel protein -center com -compound res -all

Then you can use the RMSD trajectory tool to align the protein.

In the helper directory are files to automate this procedure for MD Simulations with Desmond or OpenMM and processing with VMD.

Using PyRod

Prepare Environment

e.g.

bash (if not in a bash shell yet)

source activate pyrod (load conda environment with installed dependencies)

Run PyRod Job

PyRod uses config files located in pyrod/configs to get all necessary parameters for each job.

pyrod config.cfg

PyRod Components

Each component can be used with the provided config files. There is also a trajectory pharmacophore combo config file for running multiple components at once. Each config file is supposed to be self-explanatory. Please create an issue if you find it hard to understand a certain config file.

Test Grid

Identify proper parameters for grid placement in later trajectory analysis.

Trajectory Analysis

Analyse protein environment of water molecules and save dMIFs for Visualization and raw data for feature and exclusion volume generation.

Exclusion Volumes

Generate exclusion volumes for later pharmacophore generation based on shape dMIF.

Features

Generate features for later pharmacophore generation based on feature dMIFs.

Pharmacophore

Join exclusion volumes and features to generate a super pharmacophore with all generated features and exclusion volumes.

Trajectory Pharmacophore Combo

Run jobs for trajectory analysis and pharmacophore generation together.

Library

Generate a combinatorial pharmacophore library based on an input pharmacophore. LigandScout pharmacophores can be automatically analyzed with ROC statistics using the library_roc_analysis_LS.py script located in pyrod/helper.

dMIF Excess

Generate dMIF excess maps to investigate the effect of e.g. mutations on to the binding pocket characteristics.

Centroid

Screen the trajectories for protein conformations matching a given pharmacophore. The conformation ensemble is clustered to provide a single frame as centroid.