Integrative Modeling of Biomolecular Complexes: HADDOCKing with Cryo-Electron Microscopy Data

Abstract

Protein-protein interactions play a central role in all cellular processes. Insight into their atomic architecture is therefore of paramount importance. Cryo-electron microscopy (cryo-EM) is capable of directly imaging large macromolecular complexes. Unfortunately, the resolution is usually not sufficient for a direct atomic interpretation. To overcome this, cryo-EM data are often combined with high-resolution atomic structures. However, current computational approaches typically do not include information from other experimental sources nor a proper physico-chemical description of the interfaces. Here we describe the integration of cryo-EM data into our data-driven docking program HADDOCK and its performance on a benchmark of 17 complexes. The approach is demonstrated on five systems using experimental cryo-EM data in the range of 8.5-21 Å resolution. For several cases, cryo-EM data are integrated with additional interface information, e.g. mutagenesis and hydroxyl radical footprinting data. The resulting models have high-quality interfaces, revealing novel details of the interactions.