Dynamic Docking Using Multicanonical Molecular Dynamics: Simulating Complex Formation at the Atomistic Level.

Multicanonical molecular dynamics (McMD)-based dynamic docking has been applied to predict the native binding configurations for several protein receptors and their ligands. Due to the enhanced sampling capabilities of McMD, it can exhaustively sample bound and unbound ligand configurations, as well as receptor conformations, and thus enables efficient sampling of the conformational and configurational space, not possible using canonical MD simulations. As McMD samples a wide configurational space, extensive analysis is required to study the diverse ensemble consisting of bound and unbound structures. By projecting the reweighted ensemble onto the first two principal axes obtained via principal component analysis of the multicanonical ensemble, the free energy landscape (FEL) can be obtained. Further analysis produces representative structures positioned at the local minima of the FEL, where these structures are then ranked by their free energy. In this chapter, we describe our dynamic docking methodology, which has successfully reproduced the native binding configuration for small compounds, medium-sized compounds, and peptide molecules.