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Step 5: Fast Switching Alchemical Simulations (HPC)

Once the starting phase-points have been generated in Step 4, we are ready to launch the second major computational and massively parallel stage in the vDSSB approach, namely the swarm of the bound state annihilation trajectories and the swarm of the unbound state growth trajectories.

Bound state

The annihilation trajectories are generated in a sub-directory fsdam to be created by the end-user of the bound state directory containing the HREM data (USER_SCRATCH/bound) and by the application script maketprQ.sh provided in the SI.zip archive attached to the JCIM note. In the specific example of the the complex PF-07321332-3CLpro, the script generates 384 folders (fsdam/bi) containing the GROMACS tpr file to switch off the ligand atomic charges in 0.375 ns, starting from the configurations generated in Step 4.
The fast switching simulations are submitted on the HPC using the batch submission script submit.slr (also provided in the SI.zip archive attached to the JCIM note) which allows:

  1. to switch off the atomic charges in 384 parallel FS trajectories according to the tpr files generated with maketprQ.sh;
  2. to generate the new tpr files in each of the fsdam/bi folders using as starting point the confout.gro configuration file of previous run;
  3. to turn off the LJ ligand-environment interactions in 0.750 ns.
maketprQ.sh and submit.slr use the mdp files transitionQ_mdp and transitionvdw.mdp also provided in SI.zip attached to the JCIM note. The bound state ligand annihilation job requires about two wall clock time hours on the Marconi100 HPC platform.

Unbound state

Using the bash script maketprvdw.sh (also provided in the SI.zip attached to JCIM note), the tpr GROMACS files to perform unbound fast switching alchemical simulations are generated in the fsdam user-created subdirectory of the main HREM directory for the unbound state USER_SCRATCH/unbound.

The script creates for 192 folders (fsdam/ui) containing the tpr files to switch on the LJ ligand-water interactions in 0.360 ns, starting from the configurations generated in Step 4. The simulations are submitted using submit.slr which allows:

  1. to switch on the LJ ligand-water interactions using the tpr files generated with maketprvdw.sh;
  2. to generate the new tpr files using as starting point the confout.gro configuration file of previous run;
  3. to turn on ligand atomic charges in 0.160 ns.

maketprvdw.sh and submit.slr use the mdp files transitionvdw.mdp and transitionQ.mdp provided in SI.zip attached to the JCIM note. The unbound ligand growth required few wall clock minutes on the Marconi100 HPC cluster.