Enhanced Sampling in Molecular Dynamics Using Metadynamics, Replica-Exchange, and Temperature-Acceleration

We review a selection of methods for performing enhanced sampling in 1 molecular dynamics simulations. We consider methods based on collective variable biasing 2 and on tempering, and offer both historical and contemporary perspectives. In collective3 variable biasing, we first discuss methods stemming from thermodynamic integration that 4 use mean force biasing, including the adaptive biasing force algorithm and temperature 5 acceleration. We then turn to methods that use bias potentials, including umbrella sampling 6 and metadynamics. We next consider parallel tempering and replica-exchange methods. We 7 conclude with a brief presentation of some combination methods. 8