Enhanced sampling of chemical and biochemical reactions with metadynamics

Metadynamics (MetaD) is a method that augments molecular dynamics (MD) calculations of all types (classical and quantum) to help systems overcome energy barriers and explore regions of phase space that would otherwise not be seen during a simulation. The method has seen wide ranging uses, and it has proven especially useful for the study of reactions in which bonds break and form. In such cases, the timescale challenges of MD are profoundly limiting, and the advent of this new paradigm for biasing simulations has proven to be incredibly useful. In this review, we set out to summarise the large body of work that uses MetaD for studying reactions so that others can more easily implement this method in their own work. After a brief introduction of the method, we provide detailed summaries of the method applied in various contexts including condensed phase and biological reactions.