A similar approach is taken by Wang et al. in the application of Hamiltonian replica exchange molecular dynamics to ligand binding. In their work, multiple replicas of a protein-ligand system were simulated in implicit solvent with varying couplings of the steric and electrostatics between replicas. To enhance conformational sampling, translational and rotational Monte Carlo moves were applied before exchange attempts. This potentially allows efficient sampling across binding modes in a single binding free energy calculation, though the use of implicit solvent was critical to the success of their instantaneous Monte Carlo moves. The POPFEP work of Jayachandran et al. proposed an alternative approach, correcting for poorly mixing sampling that resulted in highly erroneous binding pose populations by decomposing the sampled configurations into distinct poses with a Markov state model and independently computing alchemical binding free energies with respect to a common noninteracting state.