GaMD is a potential-biasing method for unconstrained enhanced sampling without the need to set predefined CV. It smooths the potential energy surface by adding a harmonic boost potential as described in the seminal paper . Its general framework makes it suitable for the development of hybrid schemes and variants, such as replica-exchange umbrella sampling GaMD (GaREUS), Ligand GaMD (LiGaMD) and Peptide GaMD (Pep-GaMD). If the system potential energy is lower than a threshold energy E, a harmonic potential energy boost is applied to smooth the potential energy surface. By denoting q ∈ R 3N the configurations, when the system potential energy U (q) is lower than a threshold energy E, a boost, which depends on U (q) is added: