Integrative Modeling of Membrane-associated Protein Assemblies

Abstract Historically, membrane protein systems have been considered as one of the most challenging systems to study with experimental structural biology techniques. Over the past years, increased number of experimental structures of membrane proteins have become available thanks in particular to advances in solid-state NMR spectroscopy and cryo-electron microscopy. This has opened the route to modeling the complexes that those membrane proteins form by methods such as docking. Most approaches developed to date are, however, not capable of incorporating the topological information provided by the membrane into the modeling process. Here, we present an integrative computational protocol for the modeling of membrane-associated protein assemblies, specifically complexes consisting of a membrane-embedded protein and a soluble partner. It combines efficient, artificial intelligence-based rigid-body docking by LightDock with a flexible final refinement with HADDOCK to remove potential clashes at the interface. We make use of an equilibrated coarse-grained lipid bilayer to represent the information encoded in the membrane in the form of artificial beads, which allows to target the docking towards the binding-competent regions. We demonstrate the performance of this membrane-driven protocol on eighteen membrane-associated complexes, whose interface lies between the membrane and either the cytosolic or periplasmic regions. In addition, we evaluate how different membrane definitions impact the performance of the docking protocol and provide a comparison, in terms of success rate, to another state-of-the-art docking software, ZDOCK. Finally, we discuss the quality of the generated models and propose possible future developments. Our membrane docking protocol should allow to shed light on the still rather dark fraction of the interactome consisting of membrane proteins.