Rigid-body assignment in integrative determination of protein complex structures

Abstract

Integrative modeling of macromolecular protein complexes typically involve representing structurally available components of the complex generated using X-ray crystallography, cryo-EM or comparative modeling, as rigid bodies, and sampling their relative spatial arrangements to generate an ensemble of models that are maximally consistent with input information. While there exist some sparse guidelines in the literature for optimizing the resolution of flexible regions used to represent missing residues within and between the rigid components, the process of defining rigid regions is entirely ad-hoc, often leading to several tedious rounds of trial and error between the computational modeler and their experimental collaborator, alternating between guessing a rigid body definition and running a computationally expensive structural sampling using this definition, until the model achieves both a desirable precision and a quantifiably good fit to input data.