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 (3CL(pro)) of SARS-CoV-2.

Automated summary

The paper presents a protocol for computing absolute dissociation free energy using GROMACS code and PLUMED library, which has been automated with a Python middleware. This protocol enables accurate estimates of dissociation constants in drug-receptor systems at the atomistic level, utilizing advanced sampling techniques and nonequilibrium alchemical methodologies. The protocol has been successfully applied to calculating the absolute dissociation free energy of PF-07321332 with the main protease (3CL(pro)) of SARS-CoV-2, showing potential for precise calculations in similar systems.