All-atom molecular dynamics simulations can capture the dynamic degrees of freedom that characterize molecular recognition, the knowledge of which constitutes the cornerstone of rational approaches to drug design and optimization. In particular, enhanced sampling algorithms, such as metadynamics, are powerful tools to dramatically reduce the computational cost required for a mechanistic description of the binding process. Here, we describe the essential details characterizing these simulation strategies, focusing on the critical step of identifying suitable reaction coordinates, as well as on the different analysis algorithms to estimate binding affinity and residence times. We conclude with a survey of published applications that provides explicit examples of successful simulations for several targets.
Keywords: Binding kinetics; Collective variables; Drug discovery; Free energy; Ligand binding; Metadynamics; Molecular dynamics.