While alchemical simulations bypass slow binding and unbinding events, they still can encounter other sampling limitations. For example, one type of alchemical transformation, done using what are called absolute binding free energy (ABFE) calculations, directly computes Δ𝐺 using the reversible work of decoupling a ligand from its binding site and then recoupling it in bulk solvent . A sampling limitation of ABFE methods is that the simulation of the bound and unbound states requires the target to relax to its preferred state both in the presence and absence of the ligand, which can be slow. Alternatively, relative binding free energy (RBFE) simulations compare pairs of ligands, A and B, to measure ΔΔ𝐺 𝐴→𝐵 . In the RBFE method, ligand A is progressively morphed into B in both the binding pocket and solvent, reducing the time required for macromolecular rearrangements since the receptor may always stay in a conformation consistent with ligand binding. However, larger RBFE transformations may be difficult and less reliable due to sampling problems such as charge changes , ring breaking , and atom insertions , while more minor perturbations improve convergence speed .