Abstract
Membrane proteins are among the most challenging systems to study with experimental structural biology techniques. The increased number of deposited structures of membrane proteins has opened the route to modeling their complexes by methods such as docking. Here, we present an integrative computational protocol for the modeling of membrane-associated protein assemblies. The information encoded by the membrane is represented by artificial beads, which allow targeting of the docking toward the binding-competent regions. 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 demonstrate the performance of this protocol on eighteen membrane-associated complexes, whose interface lies between the membrane and either the cytosolic or periplasmic regions. In addition, we provide a comparison to another state-of-the-art docking software, ZDOCK. This protocol should shed light on the still dark fraction of the interactome consisting of membrane proteins.
Highlights
Membrane proteins are among the most challenging systems to study with experimental structural biology techniques
Membrane proteins (MPs) are classified based on their association mode with biological membranes into two main groups: peripheral membrane proteins that are located on either side of the membrane and are attached to it by non-covalent interactions, and integral membrane proteins (IMPs) that are inserted into the membrane and can be either exposed on only one side of the membrane or span the entire lipid bilayer
We present an integrative computational approach for modeling membrane-associated protein assemblies that combines an efficient, swarm-based rigid-body docking by LightDock with a flexible final refinement with HADDOCK to remove potential clashes at the interface
Summary
Membrane proteins are among the most challenging systems to study with experimental structural biology techniques. MPs are classified based on their association mode with biological membranes into two main groups: peripheral membrane proteins that are located on either side of the membrane and are attached to it by non-covalent interactions, and integral membrane proteins (IMPs) that are inserted into the membrane and can be either exposed on only one side of the membrane (monotopic membrane proteins) or span the entire lipid bilayer The latter, known as transmembrane proteins (TMs), are structurally categorized as α-helical bundles or β-barrels[1]. Solid-state nuclear magnetic resonance (NMR) spectroscopy, and especially cryo-electron microscopy (cryo-EM), reaching nearatomic resolution, have become central tools to study membraneassociated protein complexes[5,6] Experimental conditions such as low-expression profiles and/or high instability outside the native membrane still makes their structural characterization challenging[7]. Despite their large representation in the proteome (in human, nearly a quarter of the genome encodes for MPs8), roughly only 1% of all deposited protein structures in the Protein Data Bank[9] (PDB) corresponds to MPs, with 1099 unique protein entries as of July 2020: https://blanco.biomol.uci.edu/
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