MxMD Best Practices

This page describes best practices derived from deploying Mixed solvent Molecular Dynamics (MxMD) workflow in drug discovery projects conducted by Schrödinger Inc., and how issues with the workflow are identified and addressed.

Preparing solutes

Use the Protein Preparation Workflow Panel to prepare your protein or nucleotide-based receptor. Remove any crystallographic ligands, ions that are not directly involved in the function, and any solvent. You can export the prepared structure as an MAE file (see Export Dialog Box for more information).

The following list provides a general overview. The specific steps and parameters may vary depending on the source of the protein structure.

1. Prepare the structure
   • Remove heteroatoms (except for essential ones like metal ions).
   • You may choose to retain essential water molecules involved in ligand binding or protein function, however, if the binding site is unknown, you may want to remove all water molecules.
   • Fill missing residue sidechains. Build missing loops (if necessary). If loops are missing, an artificial hotspot may be detected in the place of the loop.
2. Optimize Hydrogen Atoms
   • Add hydrogens based on the specified pH.
   • Refine hydrogen positions.
3. Adjust Protein States
   • Assign appropriate protonation states to residues based on the chosen pH. A physiologically relevant pH value is 7.4 for most applications.
   • Pay close attention to the treatment of metal ions and their coordination. Sometimes you may need to handle metal ion coordination.
4. Energy Minimization
   • Perform an energy minimization step to relax the protein structure and remove any steric clashes introduced during preparation.
5. Membrane-bond Receptors
   • OPM-compatible membrane proteins should be used. See https://opm.phar.umich.edu for more details.

Running MxMD Simulations

MxMD workflow can be launched within Maestro, or through the command line interface.

To run simulations through Maestro, see the Mixed Solvent MD Panel

To run simulation through the command line, see Running MxMD Simulations from the Command Line.

Outputs

The output of the MxMD workflow is a .prjzip file, which is a Maestro Project Archive format. You can load this file straight into Maestro (File → Open Project) or via the View result option in the Mixed Solvent MD Panel.

Contact

For questions and support, please contact the following team leads, or an Application Scientist:

• Schrödinger MxMD Development Team Lead: Dmitry.Lupyan@schrodinger.com