![]() The convolution of the two work histograms allows us to increase significantly the resolution of the resulting work histogram with benefit for accuracy and precision of the ADFE estimate. The n b and n u work values are combined as two independent random variables obtaining n b × n u work values, referring to the process of bringing the ligand from the bound state to the bulk solvent. vDSSB relies on the enhanced sampling of the unbound (decoupled ligand in bulk) and bound (coupled protein-bound ligand) end states, followed by the NE step, consisting of the production of two swarms of NE-independent trajectories where the ligand is gradually recoupled (unbound leg) and decoupled (bound leg) via a driven alchemical parameter λ, producing two samples of n u growth and n b annihilation work values. In brief, vDSSB is a NE variant of the alchemical technique whereby the ADFE is computed in a thermodynamic cycle as the difference of the ligand solvation free energy in the bulk solvent and in the solvated complex. ![]() Our protocol for ADFE calculation is based on the vDSSB approach. (3) Alchemical FEP, due to well known sampling issues especially at low ligand-environment coupling, (4) is generally applied in industrial applications to the calculation of relative binding free energies (RBFE), (5−8) whereby a ligand is transmuted into a strictly congeneric compound. The alchemical protocol relies on a stratification of nonphysical intermediate states gradually connecting the ligand-environment potential energy function of the target end states, (2) recovering the corresponding free energy change by a sum of free energy contributions evaluated along the stratification using free energy perturbation (FEP). In this context, the so-called alchemical approach (1) emerged recently as one of the best-automated and most widely used MD-based free energy methods. ![]() In the last decades various computational methodologies, based on molecular dynamics (MD) simulations with explicit solvent, have been devised to improve (beyond the traditional docking approach) the calculation of absolute dissociation free energy in drug receptor systems. ![]()
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