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Section 5: Adapt the scripts to your own system

The focus of this tutorial is to demonstrate the APR framework. For systems that are significantly different from the host-guest example used here, we recommend you to develop your own scripts based on a thorough understanding of the APR method and the current example. For similar systems, you can refer to the following steps for customization:

  • Place a new PDB file in the "setup/pdb" folder and then use zalign.py to generate a new align_z.pdb.
  • Place new parameter files in the "setup/param_files" folder.
  • Modify the tleap.in files in the "setup/input_files" folder accordingly.
  • Select five atoms for imposing restraints in the user input file.
  • There are small differences in Amber16 compared to the old versions in terms of writing tleap input files. If you are using Amber14 or Amber12, simply change "yes" to "no" for the "Amber16" entry in the user input file.
  • pmemd.cuda is the default executable to run MD in APR scripts. Alternatives are pmemd.MPI, pmemd, sander.MPI and sander, which can be specified with the exe_path entry in the user input file.
  • If needed, turn on host conformational restraints by changing "no" to "yes" for the "jacks" entry in the user input file.
  • Change tleap and pmemd/sander variables accordingly in the user input file.

    • And a few tips and tricks:

  • The latest release of the APR scripts and user guide are available on GitHub (https://github.com/GilsonLabUCSD/APR). If you have questions or comments about this tutorial or any part of the code, we encourage you to open an issue there.
  • The general advice for determining the restraint force constants is to use enough windows such that adding an additional window anywhere does not noticeably improve accuracy anymore. In the current example, the curvature of the attachment integration line is greatest during the initial phases of attachment, and thus it is best to place more windows there.
  • To save disk space on your computer, trajectories in the production phase of APR can be saved with all water molecules and counterions stripped. If you want to analyze the "try" trajectory, the topology file you should use is vac.prmtop instead of solvated.prmtop. If you prefer to include the entire system, you can change the value of "strip_water_ions" option in the user input file.
  • The mol2 files in the "setup/param_files" folder were generated through the RESP procedure (Bayly et al.) in the program Antechamber.
  • Always check the solvation output file solvate_tleap.log to see if the correct number of water molecules and counterions are added to the system.
  • Also check structures, trajectories, histogram of distance and disang.rest to see if restraints are added as intended.

    • In this tutorial, we have focused on applying the APR method to host-guest systems. Our recent studies indicate that the free energy method can be applied to protein-ligand systems (DOI), though the enthalpy calculations may be more challenging in the protein-ligand setting. The APR technology promises to be applicable in drug design, and useful in utilizing host-guest binding data to evaluate and optimize force fields for binding calculations.

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