Creating Maps of the Ligand Binding Landscape for Kinetics-Based Drug Discovery

Simulations of ligand-protein interactions can be very useful for drug design and to gain biological insight. Full pathways of ligand-protein binding can be used to get information about ligand binding transition states, which form the rate-limiting step of the binding and release processes. However, these simulations are typically limited by the presence of large energy barriers that separate stable poses of interest. Here we describe a simulation protocol for exploring and analyzing landscapes of ligand-protein interactions that makes use of molecular docking, enhanced molecular simulation with the weighted ensemble algorithm, and network analysis. It can be accomplished using a modest cluster of graphics processing units and freely accessible software. This protocol focuses on the construction and analysis of a network model of ligand binding poses and provides links to resources that describe the other steps in more detail. The end result of this protocol is a map of the ligand-protein binding landscape that identifies transition states of the ligand binding pathway, as well as alternative bound poses that could be stabilized with modifications to the ligand.