Calculating kinetics and pathways of protein–ligand association

While studies of protein–ligand association have mostly focused on the native complex and its stability (binding affinity), relatively little attention has been paid to the association process that precedes the formation of the complex. Here we review approaches to study the kinetics of association and association mechanisms, i.e. the probability distribution of association pathways. Selected methods are described that allow these properties to be calculated quantitatively from simulation models. We summarize some applications of these methods and finally propose a model mechanism by which proteins may efficiently screen potential ligands for those that can be natively bound.