Domain-Based Protein Docking with Extremely Large Conformational Changes

Proteins are key components in many processes in living cells, and physical interactions with other proteins and nucleic acids often form key parts of their functions. In many cases, large flexibility of proteins as they interact is key to their function. To understand the mechanisms of these processes, it is necessary to consider the 3D structures of such protein complexes. When such structures are not yet experimentally determined, protein docking has long been present to computationally generate useful structure models. However, protein docking has long had the limitation that the consideration of flexibility is usually limited to very small movements or very small structures. Methods have been developed which handle minor flexibility via normal mode or other structure sampling, but new methods are required to model ordered proteins which undergo large-scale conformational changes to elucidate their function at the molecular level. Here, we present Flex-LZerD, a framework for docking such complexes. Via partial assembly multidomain docking and an iterative normal mode analysis admitting curvilinear motions, we demonstrate the ability to model the assembly of a variety of protein–protein and protein-nucleic acid complexes.