Free-energy calculations with metadynamics: theory and practice

This chapter focuses on metadynamics, which was first introduced in 2002 and then improved with several variants in the past decade. It provides an introduction to the basic concepts of molecular dynamics and of free-energy calculations. When appropriate collective variables (CVs) are used, the free-energy landscape provides a quantitative picture of the transition in terms of reactants and products stability and transition rates. The chapter introduces a simple toy model that presents all the features of a typical real-life molecular system but still is small enough to allow the reader to readily test the concepts by means of inexpensive molecular dynamics simulations. It provides introduction of biased sampling and a practical how-to for performing a free-energy calculation with metadynamics. The chapter provides an introductory guide that allows a practitioner to choose the input parameters of a metadynamics simulation and to optimize them for his/her own specific application.