Virtual Double-System Single-Box for Absolute Dissociation Free Energy Calculations in GROMACS

We describe a step-by-step
protocol for the computation of absolute
dissociation free energy with GROMACS code and PLUMED library, which
exploits a combination of advanced sampling techniques and nonequilibrium
alchemical methodologies. The computational protocol has been automated
through an open source Python middleware (HPC_Drug) which allows one
to set up the GROMACS/PLUMED input files for execution on high performing
computing facilities. The proposed protocol, by exploiting its inherent
parallelism and the power of the GROMACS code on graphical processing
units, has the potential to afford accurate and precise estimates
of the dissociation constants in drug-receptor systems described at
the atomistic level. The procedure has been applied to the calculation
of the absolute dissociation free energy of PF-07321332, an oral antiviral
proposed by Pfizer, with the main protease (3CLpro) of
SARS-CoV-2.